| Structural highlights
Function
[AP2B1_HUMAN] Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. The AP-2 beta subunit acts via its C-terminal appendage domain as a scaffolding platform for endocytic accessory proteins; at least some clathrin-associated sorting proteins (CLASPs) are recognized by their [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif. The AP-2 beta subunit binds to clathrin heavy chain, promoting clathrin lattice assembly; clathrin displaces at least some CLASPs from AP2B1 which probably then can be positioned for further coat assembly.[1] [2] [3] [4] [ARRB1_HUMAN] Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Involved in internalization of P2RY4 and UTP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 ands subsequent recycling. Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). ERK1/2 activated by the beta-arrestin scaffold is largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Recruits c-Src/SRC to ADRB2 resulting in ERK activation. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Inhibits ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Is required for SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to internalized NK1R resulting in ERK1/2 activation, which is required for the antiapoptotic effects of SP. Is involved in proteinase-activated F2RL1-mediated ERK activity. Acts as signaling scaffold for the AKT1 pathway. Is involved in alpha-thrombin-stimulated AKT1 signaling. Is involved in IGF1-stimulated AKT1 signaling leading to increased protection from apoptosis. Involved in activation of the p38 MAPK signaling pathway and in actin bundle formation. Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. May serve as nuclear messenger for GPCRs. Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. Involved in regulation of LEF1 transcriptional activity via interaction with DVL1 and/or DVL2 Also involved in regulation of receptors other than GPCRs. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) (By similarity). Involved in IL8-mediated granule release in neutrophils.[5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Adaptor protein complex 2 alpha and beta-appendage domains act as hubs for the assembly of accessory protein networks involved in clathrin-coated vesicle formation. We identify a large repertoire of beta-appendage interactors by mass spectrometry. These interact with two distinct ligand interaction sites on the beta-appendage (the "top" and "side" sites) that bind motifs distinct from those previously identified on the alpha-appendage. We solved the structure of the beta-appendage with a peptide from the accessory protein Eps15 bound to the side site and with a peptide from the accessory cargo adaptor beta-arrestin bound to the top site. We show that accessory proteins can bind simultaneously to multiple appendages, allowing these to cooperate in enhancing ligand avidities that appear to be irreversible in vitro. We now propose that clathrin, which interacts with the beta-appendage, achieves ligand displacement in vivo by self-polymerisation as the coated pit matures. This changes the interaction environment from liquid-phase, affinity-driven interactions, to interactions driven by solid-phase stability ("matricity"). Accessory proteins that interact solely with the appendages are thereby displaced to areas of the coated pit where clathrin has not yet polymerised. However, proteins such as beta-arrestin (non-visual arrestin) and autosomal recessive hypercholesterolemia protein, which have direct clathrin interactions, will remain in the coated pits with their interacting receptors.
Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly.,Schmid EM, Ford MG, Burtey A, Praefcke GJ, Peak-Chew SY, Mills IG, Benmerah A, McMahon HT PLoS Biol. 2006 Sep;4(9):e262. PMID:16903783[21]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Nakatsu F, Ohno H. Adaptor protein complexes as the key regulators of protein sorting in the post-Golgi network. Cell Struct Funct. 2003 Oct;28(5):419-29. PMID:14745134
- ↑ Owen DJ, Collins BM, Evans PR. Adaptors for clathrin coats: structure and function. Annu Rev Cell Dev Biol. 2004;20:153-91. PMID:15473838 doi:10.1146/annurev.cellbio.20.010403.104543
- ↑ Huang F, Khvorova A, Marshall W, Sorkin A. Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference. J Biol Chem. 2004 Apr 16;279(16):16657-61. Epub 2004 Feb 25. PMID:14985334 doi:10.1074/jbc.C400046200
- ↑ Lau AW, Chou MM. The adaptor complex AP-2 regulates post-endocytic trafficking through the non-clathrin Arf6-dependent endocytic pathway. J Cell Sci. 2008 Dec 15;121(Pt 24):4008-17. doi: 10.1242/jcs.033522. Epub 2008, Nov 25. PMID:19033387 doi:10.1242/jcs.033522
- ↑ Braun L, Christophe T, Boulay F. Phosphorylation of key serine residues is required for internalization of the complement 5a (C5a) anaphylatoxin receptor via a beta-arrestin, dynamin, and clathrin-dependent pathway. J Biol Chem. 2003 Feb 7;278(6):4277-85. Epub 2002 Dec 2. PMID:12464600 doi:http://dx.doi.org/10.1074/jbc.M210120200
- ↑ Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, Larsson O. {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase. J Biol Chem. 2005 Jul 1;280(26):24412-9. Epub 2005 May 3. PMID:15878855 doi:10.1074/jbc.M501129200
- ↑ Ahn S, Wei H, Garrison TR, Lefkowitz RJ. Reciprocal regulation of angiotensin receptor-activated extracellular signal-regulated kinases by beta-arrestins 1 and 2. J Biol Chem. 2004 Feb 27;279(9):7807-11. Epub 2004 Jan 7. PMID:14711824 doi:http://dx.doi.org/10.1074/jbc.C300443200
- ↑ Kang J, Shi Y, Xiang B, Qu B, Su W, Zhu M, Zhang M, Bao G, Wang F, Zhang X, Yang R, Fan F, Chen X, Pei G, Ma L. A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription. Cell. 2005 Dec 2;123(5):833-47. PMID:16325578 doi:http://dx.doi.org/10.1016/j.cell.2005.09.011
- ↑ Barnes WG, Reiter E, Violin JD, Ren XR, Milligan G, Lefkowitz RJ. beta-Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation. J Biol Chem. 2005 Mar 4;280(9):8041-50. Epub 2004 Dec 16. PMID:15611106 doi:http://dx.doi.org/10.1074/jbc.M412924200
- ↑ Huttenrauch F, Pollok-Kopp B, Oppermann M. G protein-coupled receptor kinases promote phosphorylation and beta-arrestin-mediated internalization of CCR5 homo- and hetero-oligomers. J Biol Chem. 2005 Nov 11;280(45):37503-15. Epub 2005 Sep 6. PMID:16144840 doi:http://dx.doi.org/10.1074/jbc.M500535200
- ↑ Stalheim L, Ding Y, Gullapalli A, Paing MM, Wolfe BL, Morris DR, Trejo J. Multiple independent functions of arrestins in the regulation of protease-activated receptor-2 signaling and trafficking. Mol Pharmacol. 2005 Jan;67(1):78-87. Epub 2004 Oct 8. PMID:15475570 doi:http://dx.doi.org/10.1124/mol.104.006072
- ↑ Ren XR, Reiter E, Ahn S, Kim J, Chen W, Lefkowitz RJ. Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1448-53. Epub 2005 Jan 25. PMID:15671180 doi:http://dx.doi.org/10.1073/pnas.0409534102
- ↑ Shenoy SK, Drake MT, Nelson CD, Houtz DA, Xiao K, Madabushi S, Reiter E, Premont RT, Lichtarge O, Lefkowitz RJ. beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor. J Biol Chem. 2006 Jan 13;281(2):1261-73. Epub 2005 Nov 9. PMID:16280323 doi:http://dx.doi.org/10.1074/jbc.M506576200
- ↑ Gesty-Palmer D, Chen M, Reiter E, Ahn S, Nelson CD, Wang S, Eckhardt AE, Cowan CL, Spurney RF, Luttrell LM, Lefkowitz RJ. Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation. J Biol Chem. 2006 Apr 21;281(16):10856-64. Epub 2006 Feb 21. PMID:16492667 doi:http://dx.doi.org/10.1074/jbc.M513380200
- ↑ McLaughlin NJ, Banerjee A, Kelher MR, Gamboni-Robertson F, Hamiel C, Sheppard FR, Moore EE, Silliman CC. Platelet-activating factor-induced clathrin-mediated endocytosis requires beta-arrestin-1 recruitment and activation of the p38 MAPK signalosome at the plasma membrane for actin bundle formation. J Immunol. 2006 Jun 1;176(11):7039-50. PMID:16709866
- ↑ Wang Y, Tang Y, Teng L, Wu Y, Zhao X, Pei G. Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol. 2006 Feb;7(2):139-47. Epub 2005 Dec 25. PMID:16378096 doi:10.1038/ni1294
- ↑ Deshpande DA, Theriot BS, Penn RB, Walker JK. Beta-arrestins specifically constrain beta2-adrenergic receptor signaling and function in airway smooth muscle. FASEB J. 2008 Jul;22(7):2134-41. doi: 10.1096/fj.07-102459. Epub 2008 Mar 12. PMID:18337459 doi:http://dx.doi.org/10.1096/fj.07-102459
- ↑ Zhang X, Wang F, Chen X, Chen Y, Ma L. Post-endocytic fates of delta-opioid receptor are regulated by GRK2-mediated receptor phosphorylation and distinct beta-arrestin isoforms. J Neurochem. 2008 Jul;106(2):781-92. doi: 10.1111/j.1471-4159.2008.05431.x. Epub , 2008 Apr 17. PMID:18419762 doi:http://dx.doi.org/10.1111/j.1471-4159.2008.05431.x
- ↑ Garcia Lopez MA, Aguado Martinez A, Lamaze C, Martinez-A C, Fischer T. Inhibition of dynamin prevents CCL2-mediated endocytosis of CCR2 and activation of ERK1/2. Cell Signal. 2009 Dec;21(12):1748-57. Epub 2009 Jul 28. PMID:19643177 doi:http://dx.doi.org/S0898-6568(09)00217-4
- ↑ Cheung R, Malik M, Ravyn V, Tomkowicz B, Ptasznik A, Collman RG. An arrestin-dependent multi-kinase signaling complex mediates MIP-1beta/CCL4 signaling and chemotaxis of primary human macrophages. J Leukoc Biol. 2009 Oct;86(4):833-45. doi: 10.1189/jlb.0908551. Epub 2009 Jul 20. PMID:19620252 doi:http://dx.doi.org/10.1189/jlb.0908551
- ↑ Schmid EM, Ford MG, Burtey A, Praefcke GJ, Peak-Chew SY, Mills IG, Benmerah A, McMahon HT. Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly. PLoS Biol. 2006 Sep;4(9):e262. PMID:16903783 doi:http://dx.doi.org/10.1371/journal.pbio.0040262
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