User:Amorigno/AP2 adaptor complex
AP2 adaptor complex
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The AP2 adaptor complex is a multimeric protein that works on the cell membrane to internalize cargo in clathrin-mediated endocytosis. It is a stable complex of four adaptins which give rise to a structure that has a core domain and two appendage domains attached to the core domain by polypeptide linkers. These appendage domains are sometimes called 'ears'. The core domain binds to the membrane and to cargo destined for internalisation. The alpha and beta appendage domains bind to accessory proteins and to clathrin. Their interactions allow the temporal and spatial regulation of the assembly of clathrin-coated vesicles and their endocytosis.
The AP2 adaptor complex is functionally regulated by conformational changes and phosphorylation state modification. AdaptiN Ear-binding Coat-Associated Proteins (NECAPs) dephosphorylate the complex, rendering it inactive.[1][2]
The AP-2 complex is a heterotetramer consisting of two large adaptins (α and β), a medium adaptin (μ), and a small adaptin (σ):
Complex 2 subunits:
Structure
[edit]The AP2 adaptor complex exists in two primary conformations: the open conformation (active state) and the closed conformation (inactive state).[4] In its active state, the clathrin binding site found on the β subunit and the cargo binding site found on the μ subunit are exposed to the cytosol[4], allowing their respective interactions to occur. In its inactive state, the complex experiences a conformational change that causes both sites to be covered, preventing its primary functions.[2] The α and β heavy chains of the complex make up about 60% of the polypeptide sequence of AP2 and are tightly structured into 14 HEAT repeats which form zigzagging α-helical structures that interact with the helical "legs" of the clathrin trimer.[5][4]
Function
[edit]AP2 facilitates the assembly of clathrin lattices when endocytosis needs to occur, by aggregating together with other AP2 complexes, in their active conformation.[5] These AP2 aggregates interact with individual clathrin proteins by their β-active sites, orienting them into the clathrin "cages" that form the endocytic coat.[5]
Regulation
[edit]The regulation of AP2 activity is primarily done through conformational rearrangements of the structure into two distinct (and a potential third) conformations. The "open" conformation is the active state of the complex, as the "pits" or active binding sites for clathrins and the cargo are uncovered. On the other hand, the "closed" conformation is denoted by the closing or inaccessibility of these same sites.[1] The third conformation has been described as a "hyper-open" conformation, caused by the hijacking of the AP2 adaptor complex by invasive viruses such as HIV.[6]
Activation
[edit]The presence of clathrins have been found to induce binding to cargo, and similarly, presence of cargo appears to induce clathrin binding. This is thought to occur by a secondary stablization of the complex structure, which would allow partial activation, or access, to the respective pits.[7][8] Phosphatidylinositol-(4,5)-bisphosphate (PIP2) serves as a signal sequence that binds and is recognized by AP2. PIP2 can be found within liposomes containing cargo, which interact with AP2 to then bind clathrin and execute its function. In the closed form, the PIP2 binding site is exposed, allowing for the conformational regulation to occur.[9] Because of this, a certain order of slight conformational changes bring about the fully open conformation, beginning with PIP2 binding, then cargo sequence binding, and finally clathrin binding.[9] A family of proteins called muniscins are thought the be the primary allosteric activators of the AP2 adaptor complex[10], due to their prevalence in AP2 associated pits and their inhibition resulting in the decrease in AP2 mediated endocytosis.[11][12]
Deactivation
[edit]Medical Relevance
[edit]See also
[edit]References
[edit]- ^ a b Beacham, Gwendolyn M.; Partlow, Edward A.; Hollopeter, Gunther (2019-10). "Conformational regulation of AP1 and AP2 clathrin adaptor complexes". Traffic. 20 (10): 741–751. doi:10.1111/tra.12677. ISSN 1398-9219. PMC 6774827. PMID 31313456.
{{cite journal}}: Check date values in:|date=(help)CS1 maint: PMC format (link) - ^ a b Beacham, Gwendolyn M; Partlow, Edward A; Lange, Jeffrey J; Hollopeter, Gunther (2018-01-18). "NECAPs are negative regulators of the AP2 clathrin adaptor complex". eLife. 7: e32242. doi:10.7554/eLife.32242. ISSN 2050-084X. PMC 5785209. PMID 29345618.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Partlow, Edward A.; Baker, Richard W.; Beacham, Gwendolyn M.; Chappie, Joshua S.; Leschziner, Andres E.; Hollopeter, Gunther (2019-08-29). "A structural mechanism for phosphorylation-dependent inactivation of the AP2 complex". eLife. 8: e50003. doi:10.7554/eLife.50003. ISSN 2050-084X. PMC 6739873. PMID 31464684.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b c Collins, Brett M.; McCoy, Airlie J.; Kent, Helen M.; Evans, Philip R.; Owen, David J. (2002-05-17). "Molecular Architecture and Functional Model of the Endocytic AP2 Complex". Cell. 109 (4): 523–535. doi:10.1016/S0092-8674(02)00735-3. ISSN 0092-8674.
- ^ a b c Kirchhausen, Tom; Owen, David; Harrison, Stephen C. (2014-5). "Molecular Structure, Function, and Dynamics of Clathrin-Mediated Membrane Traffic". Cold Spring Harbor Perspectives in Biology. 6 (5): a016725. doi:10.1101/cshperspect.a016725. ISSN 1943-0264. PMC 3996469. PMID 24789820.
{{cite journal}}: Check date values in:|date=(help) - ^ Sundquist, Wesley, ed. (2014-02-10). "Decision letter: Structural basis of HIV-1 Vpu-mediated BST2 antagonism via hijacking of the clathrin adaptor protein complex 1". doi:10.7554/elife.02362.019.
{{cite journal}}: Cite journal requires|journal=(help)CS1 maint: unflagged free DOI (link) - ^ Ehrlich, Marcelo; Boll, Werner; Van Oijen, Antoine; Hariharan, Ramesh; Chandran, Kartik; Nibert, Max L.; Kirchhausen, Tomas (2004-09-03). "Endocytosis by random initiation and stabilization of clathrin-coated pits". Cell. 118 (5): 591–605. doi:10.1016/j.cell.2004.08.017. ISSN 0092-8674. PMID 15339664.
- ^ Rapoport, I.; Miyazaki, M.; Boll, W.; Duckworth, B.; Cantley, L. C.; Shoelson, S.; Kirchhausen, T. (1997-05-01). "Regulatory interactions in the recognition of endocytic sorting signals by AP-2 complexes". The EMBO journal. 16 (9): 2240–2250. doi:10.1093/emboj/16.9.2240. ISSN 0261-4189. PMC 1169826. PMID 9171339.
- ^ a b Kadlecova, Zuzana; Spielman, Stephanie J.; Loerke, Dinah; Mohanakrishnan, Aparna; Reed, Dana Kim; Schmid, Sandra L. (2017-01-02). "Regulation of clathrin-mediated endocytosis by hierarchical allosteric activation of AP2". The Journal of Cell Biology. 216 (1): 167–179. doi:10.1083/jcb.201608071. ISSN 1540-8140. PMC 5223608. PMID 28003333.
- ^ Reider, Amanda; Barker, Sarah L; Mishra, Sanjay K; Im, Young Jun; Maldonado-Báez, Lymarie; Hurley, James H; Traub, Linton M; Wendland, Beverly (2009-08-27). "Syp1 is a conserved endocytic adaptor that contains domains involved in cargo selection and membrane tubulation". The EMBO Journal. 28 (20): 3103–3116. doi:10.1038/emboj.2009.248. ISSN 0261-4189.
- ^ Henne, William Mike; Boucrot, Emmanuel; Meinecke, Michael; Evergren, Emma; Vallis, Yvonne; Mittal, Rohit; McMahon, Harvey T. (2010-06-04). "FCHo Proteins Are Nucleators of Clathrin-Mediated Endocytosis". Science. 328 (5983): 1281–1284. doi:10.1126/science.1188462. ISSN 0036-8075.
- ^ Cocucci, Emanuele; Aguet, François; Boulant, Steeve; Kirchhausen, Tom (2012-08). "The First Five Seconds in the Life of a Clathrin-Coated Pit". Cell. 150 (3): 495–507. doi:10.1016/j.cell.2012.05.047. ISSN 0092-8674.
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