2g30

From Proteopedia

Revision as of 11:25, 24 March 2013

Template:STRUCTURE 2g30

beta appendage of AP2 complexed with ARH peptide

Template:ABSTRACT PUBMED 16516836

Disease

[ARH_HUMAN] Defects in LDLRAP1 are the cause of autosomal recessive hypercholesterolemia (ARH) [MIM:603813]. ARH is a disorder caused by defective internalization of LDL receptors (LDLR) in the liver. ARH has the clinical features of familial hypercholesterolemia (FH) [MIM:143890] homozygotes, including severely elevated plasma LDL cholesterol, tuberous and tendon xanthomata, and premature atherosclerosis. LDL receptor (LDLR) activity measured in skin fibroblasts is normal, as the LDL binding ability.^[1]

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.^[2][3][4][5] [ARH_HUMAN] Adapter protein (clathrin-associated sorting protein (CLASP)) required for efficient endocytosis of the LDL receptor (LDLR) in polarized cells such as hepatocytes and lymphocytes, but not in non-polarized cells (fibroblasts). May be required for LDL binding and internalization but not for receptor clustering in coated pits. May facilitate the endocytocis of LDLR and LDLR-LDL complexes from coated pits by stabilizing the interaction between the receptor and the structural components of the pits. May also be involved in the internalization of other LDLR family members. Binds to phosphoinositides, which regulate clathrin bud assembly at the cell surface.^[6]

About this Structure

2g30 is a 3 chain structure with sequence from Homo sapiens. The April 2007 RCSB PDB Molecule of the Month feature on Clathrin by Graham T. Johnson and David S. Goodsell is 10.2210/rcsb_pdb/mom_2007_4. Full crystallographic information is available from OCA.

Reference

• Edeling MA, Mishra SK, Keyel PA, Steinhauser AL, Collins BM, Roth R, Heuser JE, Owen DJ, Traub LM. Molecular switches involving the AP-2 beta2 appendage regulate endocytic cargo selection and clathrin coat assembly. Dev Cell. 2006 Mar;10(3):329-42. PMID:16516836 doi:10.1016/j.devcel.2006.01.016
• Wilmann PG, Battad J, Petersen J, Wilce MC, Dove S, Devenish RJ, Prescott M, Rossjohn J. The 2.1A crystal structure of copGFP, a representative member of the copepod clade within the green fluorescent protein superfamily. J Mol Biol. 2006 Jun 16;359(4):890-900. Epub 2006 Apr 25. PMID:16697009 doi:10.1016/j.jmb.2006.04.002
• Traub LM. Tickets to ride: selecting cargo for clathrin-regulated internalization. Nat Rev Mol Cell Biol. 2009 Sep;10(9):583-96. PMID:19696796 doi:10.1038/nrm2751

1. ↑ Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S, Bertolini S, Cossu F, Grishin N, Barnes R, Cohen JC, Hobbs HH. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science. 2001 May 18;292(5520):1394-8. Epub 2001 Apr 26. PMID:11326085 doi:10.1126/science.1060458
2. ↑ 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
3. ↑ 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
4. ↑ 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
5. ↑ 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
6. ↑ Mishra SK, Keyel PA, Edeling MA, Dupin AL, Owen DJ, Traub LM. Functional dissection of an AP-2 beta2 appendage-binding sequence within the autosomal recessive hypercholesterolemia protein. J Biol Chem. 2005 May 13;280(19):19270-80. Epub 2005 Feb 22. PMID:15728179 doi:10.1074/jbc.M501029200