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PubMed2003

Loneliness in everyday life: cardiovascular activity, psychosocial context, and health behaviors.

Prior lab research revealed higher basal total peripheral resistance (TPR) and lower cardiac output (CO) in lonely than in nonlonely young adults. In this study, experience sampling was used to obtain ambulatory blood pressure; impedance cardiography: and reports of activities, appraisals, interactions, and health behaviors. Results confirmed that loneliness predicted higher TPR and lower CO during a normal day. Loneliness did not predict differences in time spent alone, daily activities, or health behaviors but did predict higher stress appraisals and poorer social interactions. Independent of loneliness, interaction quality contributed to TPR. Loneliness differences were not mediated by depressed affect or neuroticism. Social support mediated loneliness differences in stress and threat. Concomitants of loneliness were comparable for men and women.

Adult↗

PubMed1981

Early hemodynamic and humoral effects of lofexidine.

Hemodynamic and humoral effects of lofexidine were assessed in 11 patients with essential hypertension after a total of 1.5 mg were given orally over 24 hr. Heart rate (bpm) slowed (-12 +/- 6 [SEM], p less than 0.05) and cardiac output (liters per minute) was reduced (-0.78 +/-0.18, p less than 0.01) irrespective of blood pressure response; the latter was related to changes in systemic resistance (TPR) (r = 0.72, p less than 0.01). Cardiac performance judged from ejection fraction (0.61 +/- 0.03 to 0.59 +/- 0.03, NS) and mean transit time (8.73 +/- 0.53 sec to 9.20 +/- 0.35, NS) were not altered. Plasma volume was expanded more than 10% in two patients but not changed in the others. Supine plasma catecholamines determined in five patients were reduced in all but one with no correlation to changes in either TPR or diastolic blood pressure. On the other hand, there was an increase in plasma catecholamines during head-up tilt in four of five patients, indicating normal catecholamines release. Orthostatic hypotension occurred de novo in three patients; two of them had simultaneous slowing of heart rate (vasovagal attack). Results suggested that reduction of blood pressure by lofexidine depended on lack of increase in TPR in response to reduction of cardiac output; the hemodynamic pattern of this centrally acting adrenergic blocker closely resembled that reported for beta blockers.

Adolescent↗

PubMed1988

Pharmacokinetic and pharmacodynamic interactions between nisoldipine and propranolol.

The pharmacokinetic and pharmacodynamic effects of nisoldipine, a 1,4-dihydropyridine calcium entry blocker, and the lipophilic beta-adrenoceptor blocker propranolol were assessed alone and in combination in 12 healthy men. Oral nisoldipine, 20 mg, or placebo was followed 1 hour later by propranolol, 40 mg, or placebo using a randomized, crossover, double-blind design. Nisoldipine significantly increased the AUC (+43%) and peak plasma drug concentration (Cmax) (+68%) of propranolol resulting in a higher degree of beta-adrenoceptor blockade (as assessed by isoproterenol). Conversely, nisoldipine's AUC (+30%) and Cmax (+57%) were increased with concomitant administration of propranolol. Nisoldipine did not affect blood pressure but caused significant decrease in total peripheral resistance (TPR) and increases in plasma catecholamines and cardiac index. Forearm vascular resistance and blood flow changed more markedly than did TPR and cardiac index. In contrast, propranolol had little effect on forearm hemodynamics despite significant decreases in cardiac index and increases in TPR. The data are compatible with changes in hepatic blood flow, accounting for the pharmacokinetic interaction of nisoldipine and propranolol. Different vascular beds appear to contribute to the effects of nisoldipine vs. propranolol on peripheral resistance.

Adult↗

PubMed2005

Leptin is favourably associated with vascular function in obese Caucasians, but not in obese Africans.

The comparison of the associations between chronically elevated leptin levels and cardiovascular function in obese Africans and Caucasians has not yet been determined. Therefore, the aim of this study was to compare leptin's associations with cardiovascular function in obese African and obese Caucasian women to determine whether leptin's associations differ between these two groups. This study consisted of two case-case control studies. The first study included a sample of 102 apparently healthy African women and the second, 115 apparently healthy Caucasian women. All lean and obese subjects were selected from each study. The Finometer apparatus was used to obtain a more elaborate cardiovascular profile. Serum leptin levels, insulin levels and the lipid profile were determined. Stroke volume (SV) and cardiac output (CO) were significantly (P< or =0.01) elevated in both obese African and Caucasian groups compared to their lean controls. Total peripheral resistance (TPR) was significantly decreased and arterial compliance (C(W)) significantly increased in both obese African and Caucasian groups. In the obese Caucasian group, diastolic blood pressure (DBP) was significantly (P< or =0.01) lower, SV and C(W) significantly higher (P< or =0.01) and TPR significantly lower compared to the age, body mass index (BMI), and leptin-matched obese African group. After adjusting for age and BMI, leptin correlated negatively with DBP (P< or =0.05; r=-0.33) and TPR (P< or =0.05; r=-0.36) in the obese Caucasian group, but not in the obese African group. Even though leptin levels were similar in obese African and Caucasian women, leptin is favourably associated with vascular function in obese Caucasians, but not in obese Africans.

Adult↗

PubMed1998

Signaling requirements for oncogenic forms of the Met tyrosine kinase receptor.

The Met tyrosine kinase receptor has been implicated in human cancer. Here we have examined the signaling requirements of three oncogenic forms of this molecule: wild type Met in response to ligand/autocrine stimulation, Met which has been mutationally activated, and Tpr-Met (a constitutively active truncated Met fusion protein). Previous studies have demonstrated the importance of a Grb2 binding site, and of specific tyrosine residues (i.e. Y8,9 and Y14,15) for Met function, and we have now explored the relevance of these and other sites for oncogenic Met signaling. Following substitution of various intracellular tyrosines for phenylalanine, we find that the transforming activity of each Met oncogene is dependent upon tyrosines Y8,9 and Y14,15, in addition to two novel tyrosines (Y6 and Y10) not previously implicated in Met signaling. Tyrosines Y6 and Y10 influence a variety of Met-mediated responses both in vitro (transformation, mitogenicity and invasion), and in vivo (tumorigenicity and metastasis). We also show that Tpr-Met is much more dependent on its Grb2 binding site for biological activity than are the other oncogenic forms of the Met receptor. Thus, although the three Met oncogenes examined are similar in their dependency on a number of specific tyrosines for activity, the signaling strategy employed by Tpr-Met can be differentiated from that of the other two.

3T3 Cells↗

PubMed1976

Valsalva vasoconstrictor reflex in human hypertension in after beta-adrenoreceptor blockade in conscious rabbits.

1. A Valsalva-like manoeuvre was used to elicit graded rises in total peripheral resistance (TPR) in conscious rabbits. The rises were reflex and mediated through sympathetic constrictors. Propranolol infused at different rates reaching plasma concentrations up to 240 (SEM 33) ng/ml had no effect on this reflex but reduced mean arterial pressure. However, the response was attenuated by clonidine in a dose-dependent manner. 2. Valsalva manoeuvres were used to elicit graded sympathetically mediated rises in TPR index in twenty-nine subjects with mean arterial pressure ranging from 75 to 165 mmHg. Absolute sensitivity of the constrictor response increased with rising resting TPR index, resulting in some enhancement of constrictor responses in the hypertensive subjects. It seems likely that non-autonomic factors (e.g. vessel structure) rather than hyperactive neural constrictor effects are involved in the enhanced constrictor responses in essential hypertension.

Adrenergic beta-Antagonists↗

PubMed1999

Effects of intracranial hypertension on steady and pulsatile haemodynamics in dogs.

1. Intracranial hypertension (ICH) tends to elicit various cardiovascular changes. Previous studies on the haemodynamic responses to ICH have been confined mainly to measurements of arterial pressure (AP), cardiac output (CO) and total peripheral resistance (TPR). In the present study, we used the technique of arterial impedance analysis for a complete assessment of steady and pulsatile haemodynamics in ICH. 2. In anaesthetized dogs, aortic pressure and flow waves were obtained with high-fidelity Millar sensors. The pressure and flow waves were subjected to Fourier transformation (frequency analysis) for an analysis of impedance spectra. Intracranial pressure (ICP) was elevated by inflation of an epidural balloon. At an ICP of 50 mmHg, the changes in steady and pulsatile haemodynamics were slight. 3. Haemodynamic changes became evident at an ICP of 100 mmHg. The mean AP was elevated by 31 mmHg (+32%) and heart rate (HR) was reduced by 25 b.p.m. (-18%). There was also a significant decrease in CO by 27% and large increase in TPR by 82%. With respect to pulsatile haemodynamics, an elevation of ICP to 100 mmHg caused significant increases in characteristic impedance by 45% and wave reflection by 53%. Arterial compliance was reduced by 50%. The ventricular oscillatory work was increased without a significant change in steady work. 4. The results indicate that ICH causes constriction of resistance vessels to affect AP and TPR. Because the pulsatile haemodynamics reflect mainly the Windkessel functions, ICH also induces stiffness of the large vessels to affect arterial impedance, pulse wave reflection and ventricular oscillatory work.

Animals↗

PubMed2001

Circulatory hypokinesis and functional electric stimulation during standing in persons with spinal cord injury.

OBJECTIVE: To evaluate the effects of functional electric stimulation (FES) of lower limb muscles during 30 minutes of upright standing on the central and peripheral hemodynamic response in persons with spinal cord injury (SCI). DESIGN: A repeated-measure design. Subjects were used as their own control and underwent 2 testing protocols of FES-augmented standing (active standing) and non-FES standing (passive standing). SETTING: Rehabilitation hospital. PARTICIPANTS: Fourteen individuals with SCI (7 with tetraplegia, 7 with paraplegia). INTERVENTIONS: During active standing, FES was administered to 4 muscle groups of each leg in an overlapping fashion to produce a pumping mechanism during standing. During passive standing, subjects stood for 30 minutes using a standing frame with no FES intervention. MAIN OUTCOME MEASURES: Central hemodynamic responses of stroke volume, cardiac output, heart rate, arterial blood pressure, total peripheral resistance (TPR), and rate pressure product (RPP) were evaluated by impedance cardiography. All measurements were performed during supine and sitting positions before and after standing, and during 30 minutes of upright standing. RESULTS: Comparisons between the groups with paraplegia and tetraplegia showed a significant increase in heart rate in the paraplegics after 30 minutes of active standing. During active standing, paraplegics' heart rate increased by 18.2% (p = .015); during passive standing, it increased by 6% (p = .041). TPR in the tetraplegics significantly (p = .003) increased by 54% when compared with the paraplegics during passive standing. Overall, the tetraplegic group had a significantly lower systolic blood pressure (p = .013) and mean arterial pressure (p = .048) than the paraplegics during passive standing. These differences were not detected during active standing. When data were pooled from both groups and the overall groups response to active and passive standing were compared, the results showed that cardiac output, stroke volume, and blood pressure significantly decreased (p < .05) during 30 minutes of passive standing, whereas TPR significantly increased (p < .05). All of the hemodynamic variables were maintained during 30 minutes of active standing, and there were increases in RPP and heart rate after 30 minutes of active standing. CONCLUSION: FES of the lower extremity could be used by persons with SCI as an adjunct during standing to prevent orthostatic hypotension and circulatory hypokinesis. This effect may be more beneficial to those with tetraplegia who have a compromised autonomic nervous system and may not be able to adjust their hemodynamics to the change in position.

Adult↗

PubMed2000

Dysrhythmia hazard after hospitalization for myocardial infarction: two ECG prognostic methods compared.

We retrieved reports of heart rate variability and signal-averaged electrocardiograms (SAECG) used to predict risk of a dysrhythmic event. From each report the number of cases with and without events was extracted to establish accurate values for true positive rate (tpr = sensitivity) and false positive rate (fpr = 1 minus specificity). For all the heart rate variability reports, these values were collected and tpr values were plotted versus fpr. The (fpr,tpr) data were summarized by a meta ROC graph using the method of Moses and Shapiro. A composite weighted mean value and 95% confidence interval were also derived. A summary meta-ROC curve for the SAECG reports was similarly obtained., Meta-ROC analysis of multiple reports better summarizes the performances of different prognostic methods and allows the effect of combining tests for a larger population to be simulated.

Arrhythmias, Cardiac↗

PubMed1975

[Comparing studies on the influence of dopamine and orciprenaline on cardiac and renal function of patients after cardiac surgery (author's transl)].

Cardiac and circulatory function (cardiac output, stroke volume, heart rate, mean arterial pressure = MAP, total peripheral resistance = TPR), further renal function (PAH- and inulin clearance, filtration fraction, urinary excretion, renal sodium- and potassium excretion) were measured on 15 patients undergoing cardiac surgery to whom Dopamine and Orciprenaline were administered in increasing doses of 100 mug - up to 500 mug/min (Dopamine) and 10 mug - to 20 mug/min (Orciprenaline). An infusion of Dopamine up to 250 mug/min caused a dosis-related increase of the cardiac output up to 31% (2P less than 0.001) without essential increasing of the MAP and of the heart rate. Dopamine caused a decrease of the TPR up to 24%. Doses of Dopamine over 250 mug/min cause an increase of the MAP and of the heart rate without a real increase of the cardiac output. Renal function improved under increasing doses of Dopamine, effective renal plasma flow (ERPF) up to 74%, urinary excretion up to 130%, sodium and potassium excretion up to 60% respectively. After administering Orciprenaline in a dosis of 20 mug/min cardiac output increases up to 28%, MAP and heart rate up to 12% and 17% respectively. After the administration of Orciprenaline (20 mug/min) and Dopamine (500 mug/min) frequent extra systoles were observed without any increase of the cardiac output; MAP increased by 12%, TPR decreased by 16% after 20 mug/min of Orciprenaline. ERPF decreased slightly after Orciprenaline. Urinary excretion was reduced by a half.

Aminohippuric Acids↗

PubMed2005

No association between ACE I/D polymorphism and cardiovascular hemodynamics during exercise in young women.

The ACE I/D polymorphism has been shown to interact with habitual physical activity levels in postmenopausal women to associate with submaximal and with maximal exercise hemodynamics. This investigation was designed to assess the potential relationships between ACE genotype and oxygen consumption (VO2), cardiac output (Q), stroke volume (SV), heart rate (HR), blood pressure (BP), total peripheral resistance (TPR), and arteriovenous oxygen difference ([a-v]O2 diff) during submaximal and maximal exercise in young sedentary and endurance-trained women. Seventy-seven 18-35-yr-old women underwent a maximal exercise test and a number of cardiac output tests on a treadmill using the acetylene rebreathing technique. ACE genotype was not significantly associated with VO2max (II 41.4+/-1.2, ID 39.8+/-0.9, DD 39.8+/-1.1 ml/kg/min, p=ns) or maximal HR (II 191+/-2, ID 191+/-1, DD 193+/-2 bpm, p=ns). In addition, systolic and diastolic BP, (a-v)O2 diff, TPR, SV, and Q during maximal exercise were not significantly associated with ACE genotype. During submaximal exercise, SBP, Q, SV, HR, TPR, and (a-v)O2 diff were not significantly associated with ACE genotype. However, the association between diastolic BP during submaximal exercise and ACE genotype approached significance (p=0.08). In addition, there were no statistically significant interactions between ACE genotype and habitual physical activity (PA) levels for any of the submaximal or the maximal exercise hemodynamic variables. We conclude that the ACE I/D polymorphism was not associated, independently or interacting with habitual PA levels, submaximal, or maximal cardiovascular hemodynamics in young women.

Adolescent↗

PubMed2005

Structure and ESCRT-III protein interactions of the MIT domain of human VPS4A.

The VPS4 AAA ATPases function both in endosomal vesicle formation and in the budding of many enveloped RNA viruses, including HIV-1. VPS4 proteins act by binding and catalyzing release of the membrane-associated ESCRT-III protein lattice, thereby allowing multiple rounds of protein sorting and vesicle formation. Here, we report the solution structure of the N-terminal VPS4A microtubule interacting and transport (MIT) domain and demonstrate that the VPS4A MIT domain binds the C-terminal half of the ESCRT-III protein, CHMP1B (Kd = 20 +/- 13 microM). The MIT domain forms an asymmetric three-helix bundle that resembles the first three helices in a tetratricopeptide repeat (TPR) motif. Unusual interhelical interactions are mediated by a series of conserved aromatic residues that form coiled-coil interactions between the second two helices and also pack against the conserved alanines that interdigitate between the first two helices. Mutational analyses revealed that a conserved leucine residue (Leu-64) on the third helix that would normally bind the fourth helix in an extended TPR is used to bind CHMP1B, raising the possibility that ESCRT-III proteins may bind by completing the TPR motif.

ATPases Associated with Diverse Cellular Activitie↗

PubMed1996

A model of protein targeting mediated by immunophilins and other proteins that bind to hsp90 via tetratricopeptide repeat domains.

We have shown recently that the immunophilins CyP-40 and FKBP52/hsp56 bind to a common site on hsp90 and that they exist in separate heterocomplexes with the glucocorticoid receptor (GR). FKBP52/hsp56 binds to hsp90 via its tetratricopeptide repeat (TPR) domains, it is not required for GR.hsp90 heterocomplex assembly, and it is thought to play a role in targeted movement of the GR. In this work we examine the hsp90 binding of four proteins (FKBP52/hsp56, CyP-40, p50, Mas70p) thought to be involved in targeted protein trafficking. FKBP52/hsp56 and CyP-40 (each with three TPRs), localize to the nucleus and nucleoli, respectively, and form relatively weak complexes with hsp90 that are competed by a CyP-40 fragment containing its three TPRs. The p50 component of the Src.hsp90 and Raf.hsp90 heterocomplexes localizes to cytoskeletal fibers extending from the perinuclear region to the plasma membrane and forming a rim under the plasma membrane of endothelial cells. p50, Mas70p (seven TPRs), which is a receptor for mitochondrial import, and the p60 (six to eight TPRs) component of the steroid receptor.hsp90 heterocomplex assembly system bind very tightly to hsp90 in a manner that is not competed by the CyP-40 fragment. However, bacterially expressed p60 blocks the binding of p50, Mas70p, FKBP52/hsp56, and CyP-40 to purified hsp90. The data are consistent with binding of all of these proteins to a site on hsp90 that is a general TPR domain acceptor. Our localization and binding data are used to develop a model in which proteins that are chaperoned by hsp90 move as dynamic complexes to their cellular sites of action, with the TPR-containing protein participating in targeting the movement of the complexes.

Amino Acid Sequence↗

PubMed1997

Analysis of the functional domain of the rat liver mitochondrial import receptor Tom20.

Tom20 is an outer mitochondrial membrane protein and functions as a component of the import receptor complex for the cytoplasmically synthesized mitochondrial precursor proteins. It consists of the N-terminal membrane-anchor segment, the tetratricopeptide repeat (TPR) motif, a charged amino acids-rich linker segment between the membrane anchor and the TPR motif, and the C-terminal acidic amino acid cluster. To assess the functional significance of these segments in mammalian Tom20, we cloned rat Tom20 and expressed mutant rat Tom20 proteins in Deltatom20 yeast cells and examined their ability to complement the defects of respiration-driven growth and mitochondrial protein import. Tom20N69, a mutant consisting of the membrane anchor and the linker segments, was targeted to mitochondria and complemented the growth and import defects as efficiently as wild-type Tom20, whereas a mutant lacking the linker segment did not. In vitro protein import into mitochondria isolated from the complemented yeast cells revealed that the precursor targeted to yeast Tom70 was efficiently imported into the mitochondria via rat Tom20N69. Thus the linker segment is essential for the function of rat Tom20, whereas the TPR motif and the C-terminal acidic amino acids are not.

Amino Acid Sequence↗

PubMed1998

The peptidyl-prolyl isomerase domain of the CyP-40 cyclophilin homolog Cpr7 is not required to support growth or glucocorticoid receptor activity in Saccharomyces cerevisiae.

CyP-40 cyclophilins are found in association with molecular chaperone Hsp90.steroid receptor complexes. The amino-terminal portion of these cyclophilins harbors the characteristic peptidyl-prolyl isomerase (PPIase) domain, whereas three copies of the tetratricopeptide (TPR) motif, a structure shown to be involved in protein-protein interactions, and a putative calmodulin-binding domain are located in the carboxyl-terminal half of the protein. The TPR domains mediate binding to Hsp90, but a requirement for the PPIase domain has not been established. To address this, we have investigated the effects of mutations that alter the PPIase domain of the Saccharomyces cerevisiae CyP-40 homolog, Cpr7. Because Cpr7 is required for rapid growth and full Hsp90 activity, a functional assessment of the PPIase domain could be performed in vivo. A mutation in the catalytic domain altering a conserved site predicted to be essential for isomerase activity did not compromise Cpr7 function. Furthermore, deletion of the entire PPIase domain did not significantly affect growth or Hsp90-mediated steroid receptor activity. These results indicate that the TPR-containing carboxyl terminus of Cpr7 is sufficient for fundamental Cpr7-dependent activity.

Carrier Proteins↗

PubMed1999

Different regions of the immunophilin FKBP52 determine its association with the glucocorticoid receptor, hsp90, and cytoplasmic dynein.

FKBP52 is a high molecular mass immunophilin possessing peptidylprolyl isomerase (PPIase) activity that is inhibited by the immunosuppressant drug FK506. FKBP52 is a component of steroid receptor.hsp90 heterocomplexes, and it binds to hsp90 via a region containing three tetratricopeptide repeats (TPRs). Here we demonstrate by cross-linking of the purified proteins that there is one binding site for FKBP52/dimer of hsp90. This accounts for the common heterotetrameric structure of native receptor heterocomplexes being 1 molecule of receptor, 2 molecules of hsp90, and 1 molecule of a TPR domain protein. Immunoadsorption of FKBP52 from reticulocyte lysate also yields co-immunoadsorption of cytoplasmic dynein, and we show that co-immunoadsorption of dynein is competed by a fragment of FKBP52 containing its PPIase domain, but not by a TPR domain fragment that blocks FKBP52 binding to hsp90. Using purified proteins, we also show that FKBP52 binds directly to the hsp90-free glucocorticoid receptor. Because neither the PPIase fragment nor the TPR fragment affects the binding of FKBP52 to the glucocorticoid receptor under conditions in which they block FKBP52 binding to dynein or hsp90, respectively, different regions of FKBP52 must determine its association with these three proteins.

Animals↗

PubMed2000

Role of rapsyn tetratricopeptide repeat and coiled-coil domains in self-association and nicotinic acetylcholine receptor clustering.

Rapsyn, a 43-kDa peripheral membrane protein of skeletal muscle, is essential for clustering nicotinic acetylcholine receptors (nAChR) in the postsynaptic membrane. Previous studies with rapsyn NH(2)-terminal fragments fused to green fluorescent protein, expressed in 293T cells along with nAChRs, establish the following: Rapsyn-(1-90), containing the myristoylated amino terminus and two tetratricopeptide repeats (TPRs), was sufficient for self-association at the plasma membrane; rapsyn-(1-287), containing seven TPRs, did not cluster nAChRs; whereas rapsyn-(1-360)(,) containing a coiled-coil domain (rapsyn-(298-331)), clustered nAChRs. To further analyze the role of rapsyn structural domains in self-association and nAChR clustering, we have characterized the clustering properties of additional rapsyn mutants containing deletions and substitutions within the TPR and coiled-coil domains. A mutant lacking the coiled-coil domain alone (rapsyn-(black triangle288-348)), failed to cluster nAChRs. Within the coiled-coil domain neutralization of the charged side chains was tolerated, while alanine substitutions of large hydrophobic residues resulted in the loss of nAChR clustering. Rapsyn self-association requires at least two TPRs, as a single TPR (TPR1 or TPR2 alone) was not sufficient. While TPRs 1 and 2 are sufficient for self-association, they are not necessary, as TPRs 3-7 also formed clusters similar to wild-type rapsyn. Fragments containing TPRs co-localized with full-length rapsyn, while the expressed coiled-coil or RING-H2 domain did not. These results are discussed in terms of a homology model of rapsyn, based on the three-dimensional structure of the TPR domain of protein phosphatase 5.

Animals↗

PubMed2001

Recognition of peroxisomal targeting signal type 1 by the import receptor Pex5p.

We have studied how Pex5p recognizes peroxisomal targeting signal type 1 (PTS1)-containing proteins. A randomly mutagenized pex5 library was screened in a two-hybrid setup for mutations that disrupted the interaction with the PTS1 protein Mdh3p or for suppressor mutations that could restore the interaction with Mdh3p containing a mutation in its PTS1. All mutations localized in the tetratricopeptide repeat (TPR) domain of Pex5p. The Pex5p TPR domain was modeled based on the crystal structure of a related TPR protein. Mapping of the mutations on this structural model revealed that some of the loss-of-interaction mutations consisted of substitutions in alpha-helices of TPRs with bulky amino acids, probably resulting in local misfolding and thereby indirectly preventing binding of PTS1 proteins. The other loss-of-interaction mutations and most suppressor mutations localized in short, exposed, intra-repeat loops of TPR2, TPR3, and TPR6, which are predicted to mediate direct interaction with PTS1 amino acids. Additional site-directed mutants at conserved positions in intra-repeat loops underscored the importance of the loops of TPR2 and TPR3 for PTS1 interaction. Based on the mutational analysis and the structural model, we put forward a model as to how PTS1 proteins are selected by Pex5p.

Amino Acid Sequence↗