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PubMed2002

The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170 kinase.

CLIP-170/Restin belongs to a family of conserved microtubule (MT)-associated proteins, which are important for MT organization and functions. CLIP-170 is a phosphoprotein and phosphorylation is thought to regulate the binding of CLIP-170 to MTs. However, little is known about the kinase(s) involved. In this study, we show that FKBP12-rapamycin-associated protein (FRAP, also called mTOR/RAFT) interacts with CLIP-170. CLIP-170 is phosphorylated in vivo at multiple sites, including rapamycin-sensitive and -insensitive sites, and is phosphorylated by FRAP in vitro at the rapamycin-sensitive sites. In addition, rapamycin inhibited the ability of CLIP-170 to bind to MTs. Our observations suggest that multiple CLIP-170 kinases are involved in positive and negative control of CLIP-170, and FRAP is a CLIP-170 kinase positively regulating the MT-binding behavior of CLIP-170.

Animals↗

PubMed2000

The functional role of class II-associated invariant chain peptide (CLIP) in its ability to variably modulate immune responses.

During the process of class II MHC assembly and cell surface expression, the class II-associated invariant chain peptide (CLIP) is removed from the peptide-binding groove of MHC, a task mediated by H-2M. This allows binding and presentation of peptide epitopes. We have previously shown that exogenously added CLIP interferes with this process and down-regulates the cell surface expression of class II molecules. In this study, we explored the effect of exogenously added CLIP on antigen-specific immune responses. In vivo studies with CLIP and various peptide and protein antigens with different affinities for I-A(d) molecules demonstrated that CLIP variably affects the T cell-mediated immune responses. Immunization with CLIP along with the antigen induced a shift from a T(h)1- to T(h)2-like response as determined by the cytokine profile and antibody isotype. These results suggest that the presence of exogenous CLIP can significantly influence the presentation of antigen by class II MHC molecules to CD4 T cells and thereby modulate immune responses. Exogenously added CLIP rapidly localized into the subcellular compartment of antigen-presenting cells where MHC class II molecules are present. We suggest that exogenous CLIP reduces the loading of peptides on the class II molecules, thus down-regulating MHC-peptide complexes on the cell surface. Alternatively, CLIP may bind to cell surface class II molecules and this complex is rapidly internalized resulting in reduced cell surface MHC class II expression. The reduced level of MHC-peptide complexes favors the activation of T(h)2 cells over T(h)1 cells. These results have implications in the regulation of immune responses, particularly the prevention of certain autoimmune diseases where T(h)1-type responses are pathogenic and T(h)2-type responses are protective.

Animals↗

PubMed2000

Regulation of the renal endothelin system in the two-kidney, one clip renal hypertensive rat.

Renovascular hypertension in the two-kidney, one clip (2K1C) model is characterized by initially elevated angiotensin-II (A-II) plasma concentrations, caused by ischemia in the clipped kidney and shear stress in the nonclipped kidney. These features are known stimuli of the endothelin (ET) system. The aim of this study was to analyze whether the renal ET system is activated in 2K1C renal hypertension in the rat. Wistar Kyoto rats (9 weeks old) were randomly assigned to four groups. Groups 1 and 3 underwent renal artery clipping, groups 2 and 4 were sham-operated. Groups 1 and 2 were used for analysis at 10 days after clipping, groups 3 and 4 12 weeks after clipping. We measured immunoreactive ET-1 renal tissue concentration as well as the ET(A)- and ET(B)-receptor density and affinity in renal cortex and medulla. We detected an increased immunoreactive ET-1 tissue concentration compared to the sham-operated control in the renal cortex of the nonclipped kidney 10 days (25.6 +/- 12.0 pg/g vs 12.5 +/- 5.0, 1 pg/g; p < 0.05) and in the renal cortex of the clipped kidney 90 days after clipping (92.4 +/- 47 pg/g vs 22.9 +/- 21 pg/g; p < 0.05), An increased ET(A)-receptor density was revealed in the renal medulla of the clipped kidney 10 days (624 +/- 130 fmol/mg vs 276 +/- 68 fmol/mg; p < 0.05) and 90 days (859 +/- 131 fmol/mg vs 493 +/- 93 fmol/mg; p < 0.05) after clipping. There were no differences in ET(B)-receptor density or binding affinity of either ET(A)- or ET(B)-receptors. In the 2K1C rat model of renovascular hypertension the renal ET system is activated. This activation is time-dependent and also dependent on the specific pathophysiological condition (clipped vs nonclipped). Increased ET-1 tissue concentration and upregulation of ET(A)-receptor density might lead to a synergistic activation of the ET system.

Animals↗

PubMed1997

Tissue marking clip for stereotactic breast biopsy: initial placement accuracy, long-term stability, and usefulness as a guide for wire localization.

PURPOSE: To determine initial placement accuracy, long-term stability, and usefulness as a guide for wire localization for metallic marker clips placed percutaneously after stereotactic breast biopsy. MATERIALS AND METHODS: One hundred forty-nine marker clips were placed percutaneously with a straight-needle or through-probe method, and clip positions were measured. The locations of 31 marker clips were followed up from deployment to first follow-up mammography. Thirty-six biopsy sites with marker clips were excised surgically and examined; 18 of these marker clips were targets for wire localization. The locations of 22 benign lesions were measured over time to calibrate the measurement system. RESULTS: Baseline variability was 8 mm. Initial marker clip deployment averaged 5 mm above baseline from the center of the target lesion (P < or = .01). Compared with baseline variability, marker clips remained in place from initial deployment to first imaging follow-up (mean, 8.6 months). Potentially clinically meaningful misplacement rates (deployment > 24 mm from target lesion center) were 7% for the through-probe method and 11% for the straight-needle method (not significantly different; P = .33). CONCLUSION: The marker clips appear to be useful targets for wire localization when the entire target lesion is removed at directional, vacuum-assisted breast biopsy. Upright, two-view mammography is recommended after deployment of the marker clip to document location.

Adult↗

PubMed2001

Metallic clip deployment during stereotactic breast biopsy: retrospective analysis.

PURPOSE: To determine the visibility of presumably excised lesions on screen-film mammograms obtained after biopsy and to determine the accuracy of clip deployment on the basis of measurements obtained on routine pre- and postbiopsy mammograms. MATERIALS AND METHODS: One hundred eleven cases of core-needle biopsy with clip deployment were reviewed. In each, the type of lesion, lesion location, and biopsy approach were recorded. Pre- and postbiopsy images were reviewed, and the distance between the clip and biopsy site was measured. Postbiopsy images were reviewed to determine whether the targeted lesion remained visible. RESULTS: In 62 (56%) cases, the clip was located within 5 mm of the target on postbiopsy images (craniocaudal and mediolateral), while in 18 (16%), the clip was within 6-10 mm on one projection. However, 31 (28%) clips were more than 1 cm from the target on at least one postbiopsy image. Of the 111 cases, 39 (35%) were malignant or atypical and required excision. Of these, 18 (46%) had clips at least 1 cm from the targeted lesion on at least one projection. CONCLUSION: Metallic clips placed during core-needle breast biopsy are intended to mark the biopsy site when the visible lesion is excised, in case additional biopsy is required. The data suggest that the position of metallic clips placed during stereotactic core-needle biopsy may differ substantially from the location of the biopsy site. Postbiopsy mammography should be performed in two orthogonal planes to document clip position relative to the biopsy site.

Biopsy, Needle↗

PubMed2002

Prediction of recurrence and prognosis in patients with hepatocellular carcinoma after resection by use of CLIP score.

AIM: The survival time of patients with hepatocellular carcinoma (HCC) after resection is hard to predict. Both residual liver function and tumor extension factors should be considered. A new scoring system has recently been proposed by the Cancer of the Liver Italian Program (CLIP). CLIP score was confirmed to be one of the best ways to stage patients with HCC. To our knowledge, however, the literature concerning the correlation between CLIP score and prognosis for patients with HCC after resection was not published. The aim of this study is to evaluate the recurrence and prognostic value of CLIP score for the patients with HCC after resection. METHODS: A retrospective survey was carried out in 174 patients undergoing resection of HCC from January 1986 to June 1998. Six patients who died in the hospital after operation and 11 patients with the recurrence of the disease were excluded at 1 month after hepatectomy. By the end of June 2001, 4 patients were lost and 153 patients with curative resection have been followed up for at least three years. Among 153 patients, 115 developed intrahepatic recurrence and 10 developed extrahepatic recurrence, whereas the other 28 remained free of recurrence. Recurrences were classified into early (< or =3 year) and late (>3 year) recurrence. The CLIP score included the parameters involved in the Child-Pugh stage (0-2), plus macroscopic tumor morphology (0-2), AFP levels (0-1), and the presence or absence of portal thrombosis (0-1). By contrast, portal vein thrombosis was defined as the presence of tumor emboli within vascular channel analyzed by microscopic examination in this study. Risk factors for recurrence and prognostic factors for survival in each group were analyzed by the chi-square test, the Kaplan-Meier estimation and the COX proportional hazards model respectively. RESULTS: The 1-, 3-, 5-, 7-,and 10-year disease-free survival rates after curative resection of HCC were 57.2%, 28.3%, 23.5%, 18.8%, and 17.8%, respectively. Median survival time was 28, 10, 4, and 5 mo for CLIP score 0, 1, 2, 3, and 4 to 5, respectively. Early and late recurrence developed in 109 patients and 16 patients respectively. By the chi-square test, tumor size, microsatellite, venous invasion, tumor type (uninodular, multinodular, massive), tumor extension (< or = or >50% of liver parenchyma replaced by tumor), TNM stage, CLIP score, and resection margin were the risk factors for early recurrence, whereas CLIP score and Child-Pugh stage were significant risk factors for late recurrence. In univariate survival analysis, Child-Pugh stages, resection margin, tumor size, microsatellite, venous invasion, tumor type, tumor extension, TNM stages, and CLIP score were associated with prognosis. The multivariate analysis by COX proportional hazards model showed that the independent predictive factors of survival were resection margins and TNM stages. CONCLUSION: CLIP score has displayed a unique superiority in predicting the tumor early and late recurrence and prognosis in the patients with HCC after resection.

Adolescent↗

PubMed2000

An evaluation of the relevance of routine DNA typing of fingernail clippings for forensic casework.

DNA extracted from fingernail clippings of victims in forensic cases is a possible source of DNA from the perpetrator in cases where victims struggled or defended themselves. The source of this DNA on a victim's fingernails could possibly originate from contact with the suspect's blood, saliva, semen or scratched skin. In this technical note we evaluate the relevance of routine DNA typing of fingernail clippings in the forensic biology laboratory when, in real casework, normally only small quantities of nail material is sent. This was carried out by extracting DNA from fingernail clippings from a number of volunteers, before and after aggressively scratching other volunteers. No blood was drawn from the scratching, but skin flakes were observed under the nails before cutting and subsequent DNA typing. The DNA extracted was then typed using the STR systems: HUMTHO1, HUMTPOX and HUMCSF1PO (CTT triplex) and the system of D1S80. These profiles were compared with profiles achieved by similar typing of buccal swabs as a reference from each volunteer. In this study, the profile detected from each volunteer's clippings was the same before and after scratching, and matched the profile of the corresponding volunteer as defined by typing each volunteer's reference buccal swab. Fingernail clippings that are sent to our lab in actual casework are usually so small that additional treatment by swabbing or removing debris from below the clipping is not possible. For this reason, in this simulation the entire clippings were used for DNA extraction, to maximize the possibility of finding an additional profile. In conclusion, the findings from this study show that although the profiles obtained when typing fingernail clippings are those of the donors themselves, we suggest that typing of fingernail clippings should be carried out in forensic cases only when relevant. We would suggest that fingernail clippings not be routinely sent to the biology laboratory as items of evidence to be tested.

Forensic Medicine↗

PubMedDate not supplied

Effects of attachment clips on occlusal force transmission in removable implant-supported overdentures and cantilevered superstructures.

Attachment clips are commonly used to provide retention for removable implant-supported overdentures. In this study, the effects of attachment clips on occlusal force transmission in four implant-supported overdentures with cantilever extensions were investigated using beam theory. Distributions of moments and of forces in overdenture, clips, cantilevered superstructure, and implants were calculated as functions of position, number, and stiffness of attachment clips. Three-, four-, and five-attachment clip configurations were analyzed. Results showed that maximum bending moments and forces in all components are strong functions of position, number, and retention of attachment clips, while the effects of attachment clip stiffness are negligible. Increasing the number of attachment clips from three to five results in a significant decrease of maximum bending moments in the superstructure and implant. For a wide range of attachment clip positioning, the maximum tensile force on the implants is as high as half the applied load. At least one attachment clip for all configurations is also subjected to tensile force, which can cause it to slip out from the superstructure and increase maximum bending moment in the superstructure and implants.

Acrylic Resins↗

PubMed1995

The ability of laparoscopic clips to withstand high intraluminal pressure.

OBJECTIVE: To determine if commercially available clips for laparoscopic surgery become displaced with high intraluminal pressures. DESIGN: In vivo model in which the splenic, renal, and mesenteric vessels together with the gallbladder of anesthetized living pigs were individually occluded using titanium and absorbable clips and then subjected to pressures of 300 mm Hg; and in vitro model in which the procedure was repeated on freshly removed human gallbladders with the attached segment of cystic duct. INTERVENTION: The intraluminal pressure of the occluded segment was increased until (1) the clip was released, (2) the vessel burst, or (3) the predetermined pressure (300 mm Hg) was obtained. RESULTS: A total of 90 clips were examined. No clip could be displaced from any porcine vessel at intraluminal pressures of up to 300 mm Hg. One vessel burst before the predetermined pressure was obtained, the clips remaining intact. Clips placed on the porcine and human models also could not be displaced by a pressure of 300 mg Hg. CONCLUSION: Commercially available titanium and absorbable clips do not disrupt when subjected to high intraluminal pressures. Postoperative bile leaks are more likely to result from necrosis of the cystic duct than displacement of the clip by the pressure within the biliary system.

Animals↗

PubMed1996

Motion and image artifacts of various intracranial aneurysm clips in a magnetic field.

Deflection angles of 36 types of Sugita intracranial aneurysm clips (Elgiloy), 2 types of Yasargil clips (Phynox), a Kirschner chip (SUS316) and a silver clip were examined by suspending each in a 1.5-tesla MRI (TOSHIBA MRT-200/FXII). Image artifacts of 5 types of intracranial aneurysm clips were also studied quantitatively with respect to their ratio of artifact/actual clip size using a spin-echo sequence with T1-weighted (Time of repetition (TR) = 500 ms, Time of echo (TE) = 20 ms) and T2-weighted (TR = 2000 ms, TE = 80 ms) images. All the Sugita clips from mini type to long type showed a deflection angle of less than 1.0 degree, the Yasargil clips less than 2.0 degrees, the Kirschner chip less than 6.0 degrees, and the silver chip did not move at all. Both brands of clips are therefore suitable for intracranial applications. The artifact size was directly proportional to the clip size and weight, though the ratio of artifact/actual width tended to decrease proportionately as the actual size and weight increased. The ratio of the width seemed slightly bigger than that of the length, but the difference did not reach statistical significance. There was no significant difference in the ratio of image artifacts/clip size between T1- and T2-weighted images.

Artifacts↗

PubMed1997

Torque-velocity relationship during cycle ergometer sprints with and without toe clips.

The torque-velocity relationship in cycling has been studied during all-out sprints (n = 6 subjects) with and without toe clips on an electronic Lode ergometer with strain gauges, to estimate the importance of the expected decrease in torque, velocity and power output. As previously found with different cycling protocols, the torque-velocity relationship was linear for all-out sprints with toe clips. A similar relationship was observed when cycling without toe clips but the torque-velocity relationship was inflected downwards at low or high velocities in several subjects who were not regular cyclists. The pulling action during the rise of the pedal at low velocities cannot explain why the torque-velocity relationship is not hyperbolic for cycling exercises with toe clips because similar relationships were observed without toe clips. The maximal power output was significantly higher during cycling with toe clips (782 W vs 668 W, P < 0.05), probably because of the pulling action at low and medium velocities as indicated by the higher value of the extrapolated maximal torque T0 (138 N x m vs 122 N x m, P < 0.05). In contrast, the maximal extrapolated velocity, V0 and peak velocity were not significantly improved by the use of toe clips. The comparison of the angle-torque patterns at low and high velocities suggested that the kinetic energy of the legs can be transformed into power output when cycling without toe clips as well as it can when cycling with toe clips.

Adult↗

PubMed1984

Avoidance of artifacts on computerized tomograms by selection of appropriate surgical clips.

Surgical clips (metallic or plastic) are frequently used for hemostasis and tumor marking. This study evaluated the radiographic and computerized tomographic appearance of different clips and their relative interference with computerized tomographic scans. Metallic clips (stainless steel, tantalum, and titanium) can all be seen on plain radiographs. Tantalum clips caused extensive distortion on computerized tomographic scans which would interfere with scan interpretation. Both stainless steel and titanium clips resulted in much less artifact and interference on computerized tomographic scans. Recent studies have suggested that there may be some risk of torsion of stainless steel clips in nuclear magnetic resonance scanners resulting in tissue damage. Absorbable plastic clips cannot be seen on plain film but are visualized on computerized tomographic scans and do not appear to cause scan artifact. Overall, we recommend the use of either titanium hemostatic clips when tumor marking on plain film is required or plastic clips when tumor marking is less important.

Evaluation Studies as Topic↗

PubMed1999

Anastomotic tissue response associated with expanded polytetrafluoroethylene access grafts constructed by using nonpenetrating clips.

PURPOSE: The gross, light microscopic, and scanning microscopic appearance of arterial and venous anastomoses in expanded polytetrafluoroethylene (ePTFE) access grafts constructed with nonpenetrating clips were compared with that of those constructed with polypropylene suture. We hypothesized that clip-constructed anastomoses would provide controlled approximation of native vessel intimal and medial components with the ePTFE grafts. We further hypothesized that anastomotic healing with clips would involve primarily an intimal cellular response, as compared with suture-constructed anastomoses in which cells within the media and adventitia walls participate. METHODS: Femoral artery to femoral vein arteriovenous (AV) grafts were constructed in five dogs using 4-mm internal diameter ePTFE graft material. Each animal received one AV graft with anastomoses constructed by using polypropylene sutures in one leg and one AV graft with anastomoses constructed with Vascular Closure System clips in the contralateral leg. Animals were given aspirin for the duration of the study, and grafts were explanted at 5 weeks. At the time of explantation, graft segments were grossly evaluated and then underwent light and scanning electron microscopic analysis. RESULTS: At the time of explantation, all access grafts were patent. Joining the ePTFE grafts to the native vessels with clips resulted in minimal vessel wall damage. The lumenal contours of the discontinuous approximation were smooth and without gross endothelial disruption. These observations are in contrast to the lumenal compromise and endothelial disturbance associated with the sutured anastomoses. Furthermore, hemostasis was achieved immediately in the clipped grafts, decreasing the incidence of perianastomic hematoma. Finally, cellular reconstitution occurred at the anastomotic cleft in both the sutured and the clipped junctions. The neointima exhibited an endothelial cell lining on the lumenal surface and the presence of alpha-smooth muscle cell actin positive cells within the subendothelial layer. CONCLUSION: Vascular Closure System clips are a viable alternative to suture for the approximation of ePTFE AV access grafts to native blood vessels. The use of the clips resulted in a more streamlined anastomosis, with decreased vessel wall damage, immediate hemostasis, and a trend toward shorter procedure times.

Animals↗

PubMed2001

[Breast-conserving surgery and irradiation for early breast cancer: value of surgical clips in the surgical cavity].

PURPOSE: To evaluate, qualitatively and quantitatively, the role of surgical clips in planning the tumor bed electron or brachytherapy boost in patients undergoing breast-conserving surgery and radiotherapy. PATIENTS AND METHODS: In 60 patients with breast cancer stage I or II, the excision cavity boundaries were marked by clips at surgery. Patients received a boost with brachytherapy (n = 51) or electron beam (n = 9) after whole breast irradiation. The boost target volume was first planned using clinical, mammography and operative information and its accuracy evaluated by screening the surgical clips and, if necessary, adjusting the field to encompass all clips and to include the scar. Dosimetry was retrospectively performed for each brachytherapy patient and for each surgical clip. RESULTS: It was necessary to modify the target volume field in 11 cases (18%). The average dose received by the surgical clips was 116.1% of the dose delivered to the reference isodose (median: 101.75%, range: 16-457%). However, dose heterogeneity was important in the same patient and between patients. CONCLUSION: Delineation of the boost target volume with surgical clips is more accurate than with clinical landmarks alone but this technique does not allow measurements of the clip-chest wall and clip-skin distances. Virtual simulation with CT-scan cuts is recommended for optimising boost planning.

Brachytherapy↗

PubMed2003

Intraaneurysmal flow changes affected by clip location and occlusion magnitude in a lateral aneurysm model.

In order to study the flow dynamic changes inside an aneurysm sac due to the partial occlusion of the aneurysm neck, velocity fields were measured using a particle image velocitimeter (PIV) in in vitro aneurysm models under the physiological flow waveform. Lateral aneurysm models arising from the curved parent vessel with different occlusion ratios and sites-e.g. no clip, 50% proximal and distal clip, and 75% proximal and distal clip-were tested. Reduced inflow and intraaneurysmal velocities may provide a better hemodynamic environment for aneurysm embolization. Comparing inflow rates and averaged intraaneurysmal velocities in the proximal and the distal clip model, they were lower in the distal clip model in cases of 50% neck occlusion, but they were lower in the proximal clip model in cases of 75% occlusion. These results suggest that clipping sites for reduced inflow and intraaneurysmal flow velocities may differ for different residual neck sizes. Less effective inflow blocking in the 75% distally clipped model may be due to the curvature of the parent artery. Therefore, not only the residual neck size and clipping site but the geometry of parent vessel significantly affect the flow fields inside the aneurysm, and subsequently the success of the aneurysm treatment.

Blood Flow Velocity↗

PubMed2003

Trans-catheter arterial chemoembolisation for hepatocellular carcinoma in patients with viral cirrhosis: role of combined staging systems, Cancer Liver Italian Program (CLIP) and Model for End-stage Liver Disease (MELD), in predicting outcome after treatment.

BACKGROUND: Trans-catheter arterial chemoembolisation (TACE) is the most common palliative treatment for hepatocellular carcinoma (HCC). The therapeutic options depend both on the characteristics of the tumour and on functional staging of the cirrhosis. AIM: To evaluate the effects of TACE on the survival of cirrhotic patients with HCC according to different staging systems [Okuda score, Cancer Liver Italian Program (CLIP) score, Model for End-stage Liver Disease (MELD) score] and in relation to the side-effects of TACE. METHODS: Fifty cirrhotic patients, 36 CTP class A and 14 class B, underwent 106 TACE treatments with mitoxantrone. Survival at 12, 24, and 36 months was evaluated. RESULTS: MELD at 12 months and CLIP at 24 months were identified as significant variables associated with survival. Combined cut-offs of CLIP and of MELD identified four subgroups of patients with different survivals, at 12, 24 and 36 months, respectively: CLIP >or= 2 and MELD >or= 10 (63%, 20% and 0%), CLIP < 2 and MELD >or= 10 (73%, 40% and 22%), CLIP >or= 2 and MELD < 10 (73%, 40% and 22%) and CLIP < 2 and MELD < 10 (100%, 63% and 50%). Post-TACE side-effects proved to have no influence on survival. CONCLUSION: In patients with poor probability of survival (CLIP >or= 2 and MELD >or= 10), TACE must be planned with a great deal of caution, while in patients with possibly good outcomes (CLIP < 2 and MELD < 10), more 'aggressive' therapy should be taken into consideration.

Adult↗

PubMed1995

Binding of major histocompatibility complex class II to the invariant chain-derived peptide, CLIP, is regulated by allelic polymorphism in class II.

Major histocompatibility complex class II-associated invariant chain (Ii) provides several important functions that regulate class II expression and function. One of these is the ability to inhibit class II peptide loading early in biosynthesis. This allows for efficient class II folding and egress from the endoplasmic reticulum, and protects the class II peptide binding site from loading with peptides before entry into endosomal compartments. The ability of Ii to interact with class II and interfere with peptide loading has been mapped to Ii exon 3, which encodes amino acids 82-107. This same region of Ii has been described as a nested set of class II-associated Ii peptides (CLIPs) that are transiently associated with class II in normal cells and accumulate in human histocompatibility leukocyte antigen-DM-negative cell lines. Currently it is not clear how CLIP and the CLIP region of Ii blocks peptide binding. CLIP may bind directly to the class II peptide binding site, or may bind elsewhere on class II and modulate class II peptide binding allosterically. In this report, we show that CLIP can interact with many different murine and human class II molecules, but that the affinity of this interaction is controlled by polymorphic residues in the class II chains. Likewise, structural changes in CLIP also modulate class II binding in an allele-dependent manner. Finally, the specificity and kinetics of CLIP binding to class II molecule is similar to antigenic peptide binding to class II. These data indicate that CLIP binds to class II in an analogous fashion as conventional antigenic peptides, suggesting that the CLIP segment of Ii may actually occupy the class II peptide binding site.

Alleles↗

PubMed1997

A continuous central motif of invariant chain peptides, CLIP, is essential for binding to various I-A MHC class II molecules.

Invariant chain (li) associates with MHC class II molecules and performs a number of crucial functions in antigen presentation. A nested set of class II-associated li peptides (CLIP) has been isolated, comprising the li sequence between residues 82 and 107. Recently, X-ray crystallographic analysis has revealed that residues 87-101 occupy the HLA-DR3 peptide-binding groove. Based on our previous results, Lee and McConnell have also proposed a model for the binding of CLIP to various mouse I-A molecules in the binding groove. CLIP sequences are able to bind many MHC class II molecules but the molecular basis of this promiscuity has not yet been resolved. We have shown recently that CLIP binding to I-A class II molecules is generally tolerant to side chain substitutions, suggesting that the backbone structure of CLIP may provide the features critical for its interaction with class II. In pursuit of this, backbone stereochemical disruptions by serial D-alanine substitutions in CLIP86-104 have been used in competitive binding assays to I-A class II molecules. These studies have revealed that the phylogenetically conserved central continuous region, CLIP91-99, is intolerant to such configurational substitutions. Experiments with truncated and frame-shift analogues of CLIP showed that for effective binding to class II, the sequence element CLIP90-100 must be incorporated into a peptide of 13 or more residues including at least three residues N-terminal to this motif. Additionally, it appears that different I-A molecules accommodate CLIP in different binding frames. These investigations of the relationship between the structure and binding of CLIP analogues lead us to propose that there is a general backbone motif of a periodic nature within the CLIP sequence that minimizes deleterious contacts and allows promiscuous binding to class II molecules.

Amino Acid Sequence↗