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PubMed1995

Signal transduction by the alpha 6 beta 4 integrin: distinct beta 4 subunit sites mediate recruitment of Shc/Grb2 and association with the cytoskeleton of hemidesmosomes.

We have examined the mechanism of signal transduction by the hemidesmosomal integrin alpha 6 beta 4, a laminin receptor involved in morphogenesis and tumor progression. Immunoprecipitation and immune complex kinase assays indicated that antibody- or laminin-induced ligation of alpha 6 beta 4 causes tyrosine phosphorylation of the beta 4 subunit in intact cells and that this event is mediated by a protein kinase(s) physically associated with the integrin. Co-immunoprecipitation and GST fusion protein binding experiments showed that the adaptor protein Shc forms a complex with the tyrosine-phosphorylated beta 4 subunit. Shc is then phosphorylated on tyrosine residues and recruits the adaptor Grb2, thereby potentially linking alpha 6 beta 4 to the ras pathway. The beta 4 subunit was found to be phosphorylated at multiple tyrosine residues in vivo, including a tyrosine-based activation motif (TAM) resembling those found in T and B cell receptors. Phenylalanine substitutions at the beta 4 TAM disrupted association of alpha 6 beta 4 with hemidesmosomes, but did not interfere with tyrosine phosphorylation of Shc and recruitment of Grb2. These results indicate that signal transduction by the alpha 6 beta 4 integrin is mediated by an associated tyrosine kinase and that phosphorylation of distinct sites in the beta 4 tail mediates assembly of the hemidesmosomal cytoskeleton and recruitment of Shc/Grb2.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Activation of the epidermal growth factor (EGF) receptor induces formation of EGF receptor- and Grb2-containing clathrin-coated pits.

In HeLa cells depleted of adaptor protein 2 complex (AP2) by small interfering RNA (siRNA) to the mu2 or alpha subunit or by transient overexpression of an AP2 sequestering mutant of Eps15, endocytosis of the transferrin receptor (TfR) was strongly inhibited. However, epidermal growth factor (EGF)-induced endocytosis of the EGF receptor (EGFR) was inhibited only in cells where the alpha subunit had been knocked down. By immunoelectron microscopy, we found that in AP2-depleted cells, the number of clathrin-coated pits was strongly reduced. When such cells were incubated with EGF, new coated pits were formed. These contained EGF, EGFR, clathrin, and Grb2 but not the TfR. The induced coated pits contained the alpha subunit, but labeling density was reduced compared to control cells. Induction of clathrin-coated pits required EGFR kinase activity. Overexpression of Grb2 with inactivating point mutations in N- or C-terminal SH3 domains or in both SH3 domains inhibited EGF-induced formation of coated pits efficiently, even though Grb2 SH3 mutations did not block activation of mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K). Our data demonstrate that EGFR-induced signaling and Grb2 are essential for formation of clathrin-coated pits accommodating the EGFR, while activation of MAPK and PI3K is not required.

Clathrin↗

PubMed2000

Negative regulation of PI 3-kinase by Ruk, a novel adaptor protein.

Class I(A) phosphatidylinositol 3-kinase (PI 3-kinase) is a key component of important intracellular signalling cascades. We have identified an adaptor protein, Ruk(l), which forms complexes with the PI 3-kinase holoenzyme in vitro and in vivo. This interaction involves the proline-rich region of Ruk and the SH3 domain of the p85 alpha regulatory subunit of the class I(A) PI 3-kinase. In contrast to many other adaptor proteins that activate PI 3-kinase, interaction with Ruk(l) substantially inhibits the lipid kinase activity of the enzyme. Overexpression of Ruk(l) in cultured primary neurons induces apoptosis, an effect that could be reversed by co-expression of constitutively activated forms of the p110 alpha catalytic subunit of PI 3-kinase or its downstream effector PKB/Akt. Our data provide evidence for the existence of a negative regulator of the PI 3-kinase signalling pathway that is essential for maintaining cellular homeostasis. Structural similarities between Ruk, CIN85 and CD2AP/CMS suggest that these proteins form a novel family of adaptor molecules that are involved in various intracellular signalling pathways.

Adaptor Proteins, Signal Transducing↗

PubMed1990

Cloning and expression of gamma-adaptin, a component of clathrin-coated vesicles associated with the Golgi apparatus.

Adaptins are the major components of adaptors, the protein complexes that link clathrin to transmembrane proteins (e.g., receptors) in coated pits and vesicles. The plasma membrane adaptor contains an alpha-adaptin subunit and a beta-adaptin subunit, while the Golgi adaptor contains a gamma-adaptin subunit and a beta'-adaptin subunit. A partial cDNA clone encoding gamma-adaptin was isolated from a bovine brain expression library by screening with antibodies, and was used to obtain a cDNA clone from a mouse brain library containing the full coding sequence. The identity of the clones was confirmed by protein sequencing. The deduced amino acid sequence of gamma-adaptin was found to be homologous to that of alpha-adaptin, with several stretches of identical amino acids or conservative substitutions in the first approximately 70 kD, and 25% identity overall. Weaker homology was seen between gamma- and beta-adaptins. Like both alpha- and beta-adaptins, gamma-adaptin has a proline and glycine-rich hinge region, dividing it into NH2- and COOH-terminal domains. A chimeric gamma-adaptin was constructed from the mouse and bovine cDNAs and transfected into Rat 1 fibroblasts. Immunofluorescence microscopy was carried out using an mAb which recognizes an epitope present on the chimera but not found on the rodent protein. The construct was found to have a distribution typical of endogenous gamma-adaptin. Using this transfection system, it should now be possible to exchange domains between alpha- and gamma-adaptins, to try to find out how adaptors are targeted to the appropriate membrane compartment of the cell, and how they recruit the appropriate receptors into the coated vesicle.

Adaptor Protein Complex gamma Subunits↗

PubMed1995

The alpha chain of the AP-2 adaptor is a clathrin binding subunit.

We have utilized a rabbit reticulocyte lysate coupled transcription-translation system to express the large subunits of the clathrin associated protein-2 (AP-2) complex so that their individual functions may be studied separately. Appropriate folding of each subunit into N-terminal core and C-terminal appendage domains was confirmed by limited proteolysis. Translated beta 2 subunit bound to both assembled clathrin cages and immobilized clathrin trimers, confirming and extending earlier studies with preparations obtained by chemical denaturation-renaturation. Translated alpha a exhibited rapid, reversible and specific binding to clathrin cages. As with native AP-2, proteolysis of alpha a bound to clathrin cages released the appendages, while cores were retained. Further digestion revealed a approximately 29-kDa alpha a clathrin-binding fragment that remained tightly cage-associated. Translated alpha a also bound to immobilized clathrin trimers, although with greater sensitivity to increasing pH than the translated beta 2 subunit. Clathrin binding by both the alpha and beta subunits is consistent with a bivalent cross-linking model for lattice assembly (Keen, J. H. (1987) Cell Biol. 105, 1989). It also raises the possibility that the alpha-clathrin interaction may have other consequences, such as modulation of lattice stability or shape, or other alpha functions.

Adaptor Proteins, Vesicular Transport↗

PubMed1996

Architecture of coatomer: molecular characterization of delta-COP and protein interactions within the complex.

Coatomer is a cytosolic protein complex that forms the coat of COP I-coated transport vesicles. In our attempt to analyze the physical and functional interactions between its seven subunits (coat proteins, [COPs] alpha-zeta), we engaged in a program to clone and characterize the individual coatomer subunits. We have now cloned, sequenced, and overexpressed bovine alpha-COP, the 135-kD subunit of coatomer as well as delta-COP, the 57-kD subunit and have identified a yeast homolog of delta-COP by cDNA sequence comparison and by NH2-terminal peptide sequencing. delta-COP shows homologies to subunits of the clathrin adaptor complexes AP1 and AP2. We show that in Golgi-enriched membrane fractions, the protein is predominantly found in COP I-coated transport vesicles and in the budding regions of the Golgi membranes. A knock-out of the delta-COP gene in yeast is lethal. Immunoprecipitation, as well as analysis exploiting the two-hybrid system in a complete COP screen, showed physical interactions between alpha- and epsilon-COPs and between beta- and delta-COPs. Moreover, the two-hybrid system indicates interactions between gamma- and zeta-COPs as well as between alpha- and beta' COPs. We propose that these interactions reflect in vivo associations of those subunits and thus play a functional role in the assembly of coatomer and/or serve to maintain the molecular architecture of the complex.

Amino Acid Sequence↗

PubMed1990

Analysis of 100-180-kDa phosphoproteins in clathrin-coated vesicles from bovine brain.

Protein kinases which co-purify with clathrin-coated vesicles are known to phosphorylate in vitro the 50-kDa subunit of the HA-II adaptor complex and upon inclusion of polylysine the beta-light chain of clathrin and polypeptides above 100 kDa. Here we relate the high molecular mass phosphoproteins to the known subunits of the adaptor protein complexes and to other clathrin-associated proteins by means of immunoprecipitation with monoclonal antibodies, two-dimensional electrophoresis, or electrophoresis in urea-sodium dodecyl sulfate-polyacrylamide gels. Our results show that some of the labeling of the 100-120-kDa region is accounted for by the beta'- and gamma-subunits of the HA-I adaptor complex, the alpha a-, and, to a lesser extent, by the beta-subunits of the HA-II adaptor complex. In addition, we found the assembly protein AP 180 and a hitherto undescribed 110-kDa coat polypeptide to be heavily phosphorylated upon release of these proteins from the coated vesicle membrane. In all cases, labeling was confined to serine residues.

Amino Acids↗

PubMed2002

Association of mumps virus V protein with RACK1 results in dissociation of STAT-1 from the alpha interferon receptor complex.

It has been reported that mumps virus protein V or the C-terminal Cys-rich region of protein V (Vsp) is associated with blocking of the interferon (IFN) signal transduction pathway through a decrease in STAT-1 production. The intracellular target of the V protein was investigated by using a two-hybrid screening system with Vsp as bait. Full-length V protein and Vsp were able to bind to RACK1, and the interaction did not require two WD domains, WD1 and WD2, in RACK1. A significant interaction between V protein and RACK1 was also demonstrated in cells persistently infected with mumps virus (FLMT cells), and the formation of the complex was not affected by treatment with IFN. On the other hand, in uninfected cells, STAT-1 was associated with the long form of the beta subunit of the alpha IFN receptor, and this association was mediated by the function of RACK1 as an adaptor protein. Immunoprecipitation and glutathione S-transferase pull-down experiments revealed that the association of RACK1 or mumps virus V protein with the IFN receptor was undetectable in mumps virus-infected cells. Furthermore, RACK1 interacted with mumps virus V protein with a higher affinity than STAT-1 did. Therefore, it is suggested that mumps virus V protein has the ability to interact strongly with RACK1 and consequently to bring about the disruption of the complex formed from STAT-1, RACK1, and the IFN receptor.

Cells, Cultured↗

PubMed2001

Assembly of the 26S proteasome is regulated by phosphorylation of the p45/Rpt6 ATPase subunit.

We investigated whether the assembly/disassembly of the 26S proteasome is regulated by phosphorylation/dephosphorylation. The regulatory complex disassembled from the 26S proteasome was capable of phosphorylating the p45/Sug1/Rpt6 subunit, suggesting that the protein kinase is activated upon dissociation of the 26S proteasome or that the phosphorylation site of p45 becomes susceptible to the protein kinase. In addition, the p45-phosphorylated regulatory complex was found to be incorporated into the 26S proteasome. When the 26S proteasome was treated with alkaline phosphatase, it was dissociated into the 20S proteasome and the regulatory complex. Furthermore, the p45 subunit and the C3/alpha2 subunit were cross-linked with DTBP, whereas these subunits were not cross-linked by dephosphorylating the 26S proteasome. These results indicate that the 26S proteasome is disassembled into the constituent subcomplexes by dephosphorylation and that it is assembled by phosphorylation of p45 by a protein kinase, which is tightly associated with the regulatory complex. It was also revealed that the p45 subunit is directly associated with the 20S proteasome alpha-subunit C3 in a phosphorylation-dependent manner.

ATPases Associated with Diverse Cellular Activitie↗

PubMed1995

Interaction of the transcriptional activator Stat-2 with the type I interferon receptor.

Binding of interferon-alpha (IFN alpha) to the multisubunit type I IFN receptor (IFNR) induces activation of the Tyk-2 and Jak-1 kinases and tyrosine phosphorylation of multiple signaling elements, including the Stat proteins that form the ISGF3 alpha complex. Although Jak kinases are required for IFN alpha-dependent activation of Stats, the mechanisms by which Stats interact with these kinases are not known. We report that Stat-2 associates with beta s subunit of the type I IFN receptor in an interferon-dependent manner. This association is rapid, occurring within 1 min of interferon treatment of cells, and is inducible by various type I (alpha, beta, omega) but not type II (gamma) IFNs. The kinetics of Stat-2-IFNR association are similar to the kinetics of phosphorylation of Stat-2, suggesting that during its binding to the type I IFNR, Stat 2 acts as a substrate for interferon-dependent tyrosine kinase activity. These findings support the hypothesis that the type I IFNR acts as an adaptor, linking Stat proteins to Jak kinases. Interaction of Stat-2 with the beta s subunit of the type I IFNR may be a critical signaling event, required for the formation of the ISGF3 alpha complex and downstream transcription of interferon-stimulated genes.

Amino Acid Sequence↗

PubMed2000

Abnormal vesicular trafficking in mouse models of Hermansky-Pudlak syndrome.

Hermansky-Pudlak Syndrome (HPS) is a group of related multigenic recessively inherited disorders which causes abnormalities in the biosynthesis and/or function of three related organelles; melanosomes, platelet-dense granules and lysosomes. These lead, in turn, to hypopigmentation, prolonged bleeding and ceroid deposition. Positional cloning strategies have identified five mouse HPS genes. Two orthologous human diseases (HPS1 and HPS2) have likewise been identified. At least four of the five mouse genes encode proteins involved in the regulation of intracellular vesicle trafficking. The pearl (HPS2) and mocha genes encode the beta3A and delta subunits, respectively, of the AP-3 adaptor complex, which captures organelle membrane proteins at the trans-Golgi apparatus. The protein products of the pallid and gunmetal genes are also important components of the vesicular trafficking machinery. The former interacts with a t-SNARE, syntaxin13, and the latter is the alpha subunit of Rab geranylgeranyltransferase, which renders Rab proteins sufficiently lipophilic to function at their target membranes. The pale ear (HPS1) gene encodes a ubiquitously expressed protein of unknown function. Recent physiological studies have shown that mouse HPS mutants, like their human HPS counterparts, have variably reduced lifespans and may have lung abnormalities.

Animals↗

PubMed1995

Monocyte colony-stimulating factor stimulates binding of phosphatidylinositol 3-kinase to Grb2.Sos complexes in human monocytes.

Monocyte colony-stimulating factor (M-CSF) is required for the proliferation of mononuclear phagocytes. The activated M-CSF receptor associates with phosphatidylinositol 3-kinase (PI 3-kinase). In the present studies, we demonstrate that M-CSF also induces direct interaction of PI 3-kinase (p85 alpha subunit) with the SH2/SH3 adaptor protein Grb2. Tyrosine-phosphorylated PI 3-kinase interacts with the SH2 domain of Grb2. A pYRNE (pY408) site in PI 3-kinase is potentially involved in this interaction. The results also demonstrate that the PI 3-kinase.Grb2 complex associates with the guanine nucleotide exchange protein Sos. Since Sos binds to the SH3 domains of Grb2 and thereby associates with Ras at the cell membrane, formation of the PI 3-kinase.Grb2.Sos complex provides a potential mechanism for growth factor-induced interactions of PI 3-kinase and Ras.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha.

The cytoplasmic adaptor protein SLP-65 (BLNK or BASH) is a critical downstream effector of the B cell antigen receptor (BCR). Tyrosine-phosphorylated SLP-65 assembles intracellular signaling complexes such as the Ca(2 +) initiation complex encompassing phospholipase C-gamma2 and Bruton's tyrosine kinase. It is, however, unclear how the SLP-65 signaling module can be recruited to the plasma membrane. Here we show that following B cell stimulation, SLP-65 associates directly with the BCR signaling subunit, the Ig-alpha / Ig-beta heterodimer. The interaction is mediated by the Src homology 2 domain of SLP-65 and the phosphorylated Ig-alpha tyrosine 204, which is located outside of the immunoreceptor tyrosine-based activation motif. Our data identify an unexpected BCR phosphorylation pattern and indicate that Ig-alpha has the capability to serve as transmembrane adaptor in BCR signaling.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Spatial regulation of Galphai protein signaling in clathrin-coated membrane microdomains containing GAIP.

Regulators of G-protein signaling (RGS) proteins are GTPase-activating proteins (GAPs) that bind to Galpha subunits and attenuate G protein signaling, but where these events occur in the cell is not yet established. Here we investigated, by immunofluorescence labeling and deconvolution analysis, the site at which endogenous Galpha-interacting protein (GAIP) (RGS19) binds to Galphai3-YFP and its fate after activation of delta-opioid receptor (DOR). In the absence of agonist, GAIP is spatially segregated from Galphai3 and DOR in clathrin-coated domains (CCPs) of the cell membrane (PM), whereas Galphai3-YPF and DOR are located in non-clathrin-coated microdomains of the PM. Upon addition of agonist, Galphai3 partially colocalizes with GAIP in CCPs at the PM. When endocytosis is blocked by expression of a dynamin mutant [dyn(K44A)], there is a striking overlap in the distribution of DOR and Galphai3-YFP with GAIP in CCPs. Moreover, Galphai3-YFP and GAIP form a coprecipitable complex. Our results support a model whereby, after agonist addition, DOR and Galphai3 move together into CCPs where Galphai3 and GAIP meet and turn off G protein signaling. Subsequently, Galphai3 returns to non-clathrin-coated microdomains of the PM, GAIP remains stably associated with CCPs, and DOR is internalized via clathrin-coated vesicles. This constitutes a novel mechanism for regulation of Galpha signaling through spatial segregation of a GAP in clathrin-coated pits.

Adaptor Protein Complex 2↗

PubMedDate not supplied

Zyxin, axin, and Wiskott-Aldrich syndrome protein are adaptors that link the cadherin/catenin protein complex to the cytoskeleton at adherens junctions in the seminiferous epithelium of the rat testis.

During spermatogenesis, the movement of germ cells across the seminiferous epithelium is associated with extensive junction restructuring. Yet the underlying mechanism (or mechanisms) that regulates these events is largely unknown. If the molecular architecture of the cell-cell actin-based adherens junction (AJ), such as ectoplasmic specialization (ES) and tubulobulbar complex- two testis-specific AJ types, is known, many functional mechanistic studies can be designed. We thus undertook an investigation to study 3 adaptors in the seminiferous epithelium: zyxin, axin, and Wiskott-Aldrich syndrome protein (WASP). All 3 adaptors were shown to be products of Sertoli and germ cells. Zyxin was shown to be a stage-specific protein that was most prominent during stages V-VII and restricted mostly to pachytene spermatocytes, but it could also be detected at the site of basal and apical ectoplasmic specialization (ES). Zyxin, axin, and WASP were shown to be structurally linked to the N-cadherin/beta-catenin/alpha-actinin/actin complex but not to the nectin-3/afadin or the beta 1-integrin-mediated protein complexes. Interestingly, zyxin, axin, and WASP are also structurally linked to vimentin (an intermediate filament protein) and alpha-tubulin (the subunit of a microtubule), which suggests that they have a role (or roles) in the regulation of the dynamics of the desmosome-like junction and microtubule. These results illustrate that zyxin, axin, and WASP are adaptors in both AJs and intermediate filament-based desmosome-like junctions. This raises the possibility that classic cadherins are also associated with vimentin-based intermediate filaments via these adaptors in the testis. While virtually no N-cadherin was found to associate with vimentin in the seminiferous tubules, it did associate with vimentin when testis lysates were used. Interestingly, about 5% of the E-cadherin associated with vimentin in isolated seminiferous tubules, and about 50% of the E-cadherin in the testis used vimentin as its attachment site. These data suggest that cadherins in the testis, unlike those in other epithelia, use different attachment sites to anchor the cadherin/catenin complex to the cytoskeleton. The levels of zyxin, axin, and WASP were also assessed during AF-2364-mediated AJ disruption of the testis, which illustrated a time-dependent protein reduction that was similar to the trends observed in nectin-3 and afadin but was the opposite of those observed for N-cadherin and beta-catenin, which were induced. Collectively, these results illustrate that while these adaptors are structurally associated with the cadherin/catenin complex in the testis, they are regulated differently.

Adherens Junctions↗

PubMed1994

Cloning of Drosophila beta-adaptin and its localization on expression in mammalian cells.

A Drosophila cDNA (BAD1) encoding a structural and assembly-competent homologue of the mammalian coated pit beta-adaptins (beta and beta') has been cloned and sequenced. In its amino-terminal region (residues 1-575), the BAD1 sequence appears intermediate between that of the mammalian beta-adaptin and a predicted sequence, from cDNA 105a, which appears to code for a version of beta'-adaptin. To test its functional characteristics, a 'myc'-tagged version of BAD1 was expressed in Cos cells. The BAD1 protein was detected most clearly in plasma membrane coated pits, where it colocalized with alpha-adaptin, although other coated pits were noted which apparently did not contain alpha-adaptin. However, these are probably gamma-adaptin containing pits, as BAD1 was also found colocalized with gamma-adaptin in Golgi coated pits in which, typically, alpha-adaptin is absent. Immunoprecipitation experiments confirmed that the BAD1 protein was present in both types of adaptor complex, unlike beta-adaptin which complexes with alpha-adaptin and beta'-adaptin which partners gamma-adaptin exclusively. In spite of this, BAD1 expression does not appear to mix alpha-adaptin and gamma-adaptin distribution amongst all the coated pits: thus the location of these adaptor complexes in mammalian cells does not depend on the differences between beta subunits but rather on membrane-specific interactions of other adaptor polypeptides. The differential interaction of beta with alpha-adaptin and beta' with gamma-adaptin in mammalian cells is likely to depend on the few non-conservative differences between their respective sequences and BAD1. Four of these (one with respect to beta and three versus 105a) are clustered in a particular region (residues 155 to 305), which may therefore represent a domain that influences the choice of partner adaptin.

Adaptor Protein Complex 1↗

PubMed1991

Subunit interaction and function of clathrin-coated vesicle adaptors from the Golgi and the plasma membrane.

Clathrin in coated vesicles is linked to transmembrane receptors by adaptor protein complexes. The Golgi-associated adaptor complex HA1 is a tetramer, made up of beta', gamma, 47-kDa, and 20-kDa subunits, whereas the tetrameric plasma membrane adaptor, HA2, contains alpha, beta, 50-kDa, and 16-kDa subunits (Ahle, S., Mann, A., Eichelsbacher, U., and Ungewickell, E. (1988) EMBO J. 7, 919-929). Here we report on the structural organization of adaptor subunits as revealed by proteolytic dissection. We show that the beta' and gamma subunits of HA1 are cleaved into 60-67-kDa "trunk" and 32-44-kDa "head" fragments. Interactions between adaptor subunits involve the trunk domains only. In overall organization of their domains, the Golgi and plasma membrane adaptors are very similar. The similarity encompasses also the location of phosphorylated serine residues in the alpha a, beta, beta', and gamma subunits, which are found in the head domains in all cases. In the alpha a and beta subunits they probably occur in the proline- and glycine-rich hinge region, which connects the head to the trunk. Identical adaptor fragments were obtained by controlled digestion of clathrin-coated vesicles. Under conditions that did not affect the integrity of the clathrin heavy chain, the adaptor head fragments were always quantitatively released from coated vesicles. The release of the bulk of the adaptors occurred concomitantly with the cleavage of their beta-type subunits (beta and beta') and under buffer conditions that prevent aggregation of adaptors. These observations taken together with the results of reconstitution experiments confirm and extend previous data (Ahle, S., and Ungewickell, E. (1989) J. Biol. Chem. 264, 20089-20093) which suggested that adaptors attach to clathrin through their beta-type (beta and beta') subunits. Moreover, high affinity interaction between adaptors and clathrin requires the participation of regions from both the head and trunk domains of the beta-type subunits.

Animals↗

PubMed2003

Conserved structural motifs in intracellular trafficking pathways: structure of the gammaCOP appendage domain.

The formation of coated vesicles is a fundamental step in many intracellular trafficking pathways. COPI and clathrin represent two important and distinct sets of vesicle coating machinery, involved primarily in mediating intra-Golgi and endocytic transport, respectively. Here we identify an important functional region at the carboxyl terminus of the gamma subunit of the COPI complex (gammaCOP) and describe the X-ray crystal structure of this domain at 2.3 A resolution. This domain of gammaCOP exhibits unexpected structural similarity to the carboxyl-terminal appendage domains of the alpha and beta subunits of the AP2 adaptor proteins, integral components of clathrin-coated vesicles. The remarkable structural conservation exhibited by the gammaCOP appendage domain, coupled with functional data and primary sequence analysis, supports a model of COPI function with significant structural and mechanistic parallels to vesicular transport by the clathrin/AP2 system.

Adaptor Protein Complex 2↗