AP2 adaptor complex

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AP-2 complex AP-2 complex.png
AP-2 complex

The AP2 adaptor complex is a multimeric protein that works on the cell membrane to internalize cargo in clathrin-mediated endocytosis. [1] 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.

Contents

The AP-2 complex is a heterotetramer consisting of two large adaptins (α and β), a medium adaptin (μ), and a small adaptin (σ):

Structure

The AP2 adaptor complex exists in two primary conformations: the open conformation (active state) and the closed conformation (inactive state). [2] 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, [2] 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. [3] 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. [4] [2]

AP2 Adaptor Complex Cryo-EM Structure. Red - alpha subunits. Blue - beta subunit. Green - mu subunit. Yellow - sigma subunit. Ap2colorcropped.jpg
AP2 Adaptor Complex Cryo-EM Structure. Red - alpha subunits. Blue - beta subunit. Green - mu subunit. Yellow - sigma subunit.

Function

AP2 facilitates the assembly of clathrin lattices when endocytosis needs to occur, by aggregating together with other AP2 complexes, in their active conformation. [4] These AP2 aggregates interact with individual clathrin proteins by their β-active sites, orienting them into the clathrin "cages" that form the endocytic coat. [4]

Regulation

The regulation of AP2 activity is primarily done through conformational rearrangements of the structure into two distinct (and a potential third and fourth) 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. [6]

Activation

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 stabilization 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 to 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] Additionally, the complex has been found to be regulated and activated by phosphorylation of its (mu) subunit. [13] [14]

Deactivation

Deactivation, or change into the "closed" conformation, is still unclear. NECAPs are thought the play a role in it, by binding to the α subunit of AP2. [6] Not much is known, but the open conformation of AP2, which is phosphorylated, appears to be necessary for NECAP1 to bind within its core. [3] The process of action is still unknown, but this interaction causes the dephosphorylation of the AP2 adaptor complex, thus deactivating it.

Medical Relevance

AP2 has been identified to intimately participate in autophagic cellular pathways, responsible for the degradation of aggregated protein. [15] In fact, it's seen to complex with phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM), which would serve as an important receptor group for microtubule-associated protein 1 light chain 3 (LC3). LC3 has an important role in some autophagic pathways. [16] Because of this, there is suspicion that AP2 deficiency or dysfunction may be a precursor for the development of familial Alzheimer's Disease. [15]

See also

Related Research Articles

<span class="mw-page-title-main">Endocytosis</span> Cellular process

Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. Endocytosis includes pinocytosis and phagocytosis. It is a form of active transport.

<span class="mw-page-title-main">Clathrin</span> Protein playing a major role in the formation of coated vesicles

Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice that surrounds the vesicle, hence the protein's name, which is derived from the Latin clathrum meaning lattice. Coat-proteins, like clathrin, are used to build small vesicles in order to transport molecules within cells. The endocytosis and exocytosis of vesicles allows cells to communicate, to transfer nutrients, to import signaling receptors, to mediate an immune response after sampling the extracellular world, and to clean up the cell debris left by tissue inflammation. The endocytic pathway can be hijacked by viruses and other pathogens in order to gain entry to the cell during infection.

<span class="mw-page-title-main">COPI</span> Protein complex

COPI is a coatomer, a protein complex that coats vesicles transporting proteins from the cis end of the Golgi complex back to the rough endoplasmic reticulum (ER), where they were originally synthesized, and between Golgi compartments. This type of transport is retrograde transport, in contrast to the anterograde transport associated with the COPII protein. The name "COPI" refers to the specific coat protein complex that initiates the budding process on the cis-Golgi membrane. The coat consists of large protein subcomplexes that are made of seven different protein subunits, namely α, β, β', γ, δ, ε and ζ.

<span class="mw-page-title-main">Receptor-mediated endocytosis</span>

Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane (invagination). This process forms vesicles containing the absorbed substances and is strictly mediated by receptors on the surface of the cell. Only the receptor-specific substances can enter the cell through this process.

<span class="mw-page-title-main">Vesicular transport adaptor protein</span>

Vesicular transport adaptor proteins are proteins involved in forming complexes that function in the trafficking of molecules from one subcellular location to another. These complexes concentrate the correct cargo molecules in vesicles that bud or extrude off of one organelle and travel to another location, where the cargo is delivered. While some of the details of how these adaptor proteins achieve their trafficking specificity has been worked out, there is still much to be learned.

<span class="mw-page-title-main">Epsin</span>

Epsins are a family of highly conserved membrane proteins that are important in creating membrane curvature. Epsins contribute to membrane deformations like endocytosis, and block vesicle formation during mitosis.

<span class="mw-page-title-main">AP2M1</span> Protein-coding gene in the species Homo sapiens

AP-2 complex subunit mu is a protein that in humans is encoded by the AP2M1 gene.

<span class="mw-page-title-main">Adaptor-related protein complex 2, alpha 1</span> Protein-coding gene in the species Homo sapiens

AP-2 complex subunit alpha-1 is a protein that in humans is encoded by the AP2A1 gene.

<span class="mw-page-title-main">AP1M1</span> Protein-coding gene in the species Homo sapiens

AP-1 complex subunit mu-1 is a protein that in humans is encoded by the AP1M1 gene.

<span class="mw-page-title-main">AP2A2</span> Protein-coding gene in the species Homo sapiens

AP-2 complex subunit alpha-2 is a protein that in humans is encoded by the AP2A2 gene.

<span class="mw-page-title-main">AP1B1</span> Protein-coding gene in the species Homo sapiens

AP-1 complex subunit beta-1 is a protein that in humans is encoded by the AP1B1 gene.

<span class="mw-page-title-main">AP2B1</span> Protein-coding gene in the species Homo sapiens

AP-2 complex subunit beta is a protein that in humans is encoded by the AP2B1 gene.

<span class="mw-page-title-main">AP1S1</span> Protein-coding gene in the species Homo sapiens

AP-1 complex subunit sigma-1A is a protein that in humans is encoded by the AP1S1 gene.

<span class="mw-page-title-main">AAK1</span> Protein-coding gene in the species Homo sapiens

Adaptor-associated protein kinase 1 also known as AP2-associated protein kinase 1 is an enzyme that in humans is encoded by the AAK1 gene and is involved in clathrin mediated endocytosis. Alternatively spliced transcript variants have been described, but their biological validity has not been determined.

<span class="mw-page-title-main">AP1S2</span> Protein-coding gene in humans

AP-1 complex subunit sigma-2 is a protein that in humans is encoded by the AP1S2 gene.

<span class="mw-page-title-main">AP2S1</span> Protein-coding gene in the species Homo sapiens

AP-2 complex subunit sigma is a protein that in humans is encoded by the AP2S1 gene.

Clathrin adaptor proteins, also known as adaptins, are vesicular transport adaptor proteins associated with clathrin. These proteins are synthesized in the ribosomes, processed in the endoplasmic reticulum and transported from the Golgi apparatus to the trans-Golgi network, and from there via small carrier vesicles to their final destination compartment. The association between adaptins and clathrin are important for vesicular cargo selection and transporting. Clathrin coats contain both clathrin and adaptor complexes that link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. Therefore, adaptor proteins are responsible for the recruitment of cargo molecules into a growing clathrin-coated pits. The two major types of clathrin adaptor complexes are the heterotetrameric vesicular transport adaptor proteins (AP1-5), and the monomeric GGA adaptors. Adaptins are distantly related to the other main type of vesicular transport proteins, the coatomer subunits, sharing between 16% and 26% of their amino acid sequence.

<span class="mw-page-title-main">Beta2-adaptin C-terminal domain</span>

The C-terminal domain ofBeta2-adaptin is a protein domain is involved in cell trafficking by aiding import and export of substances in and out of the cell.

<span class="mw-page-title-main">Muniscins</span>

The muniscin protein family was initially defined in 2009 as proteins having 2 homologous domains that are involved in clathrin mediated endocytosis (CME) and have been reviewed. In addition to FCHO1, FCHO2 and Syp1, SGIP1 is also included in the family because it contains the μ (mu) homology domain and is involved in CME, even though it does not contain the F-BAR domain

<span class="mw-page-title-main">Alpha Arrestin</span>

The arrestin family of proteins is subdivided into α-arrestins (also referred to as arrestin-related trafficking adaptors or arrestin-like yeast proteins in yeast or ARRDCs in mammals, β-arrestins and Vps26-like arrestins proteins. The α-Arrestins are an ancestral branch of the larger arrestin family of proteins and they are conserved across eukaryotes but are best characterized in the budding yeast Saccharomyces cerevisiae; to-date there are 6 α-arrestins identified in mammalian cells and 14 α-arrestins identified in the budding yeast Saccharomyces cerevisiae. The yeast α-arrestin family comprises Ldb19/Art1, Ecm21/Art2, Aly1/Art6, Aly2/Art3, Rod1/Art4, Rog3/Art7, Art5, Csr2/Art8, Rim8/Art9, Art10, Bul1, Bul2, Bul3 and Spo23. The best characterized α-arrestin function to date is their endocytic regulation of plasma membrane proteins, including G-protein coupled receptors and nutrient transporters. α-Arrestins control endocytosis of these membrane proteins in response to cellular stressors, including nutrient or metal ion excess.

References

  1. ↑ Pearse BM, Smith CJ, Owen DJ (April 2000). "Clathrin coat construction in endocytosis". Current Opinion in Structural Biology. 10 (2): 220–228. doi:10.1016/S0959-440X(00)00071-3. PMID   10753805.(subscription required)
  2. 1 2 3 Collins BM, McCoy AJ, Kent HM, Evans PR, Owen DJ (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 . PMID   12086608.
  3. 1 2 Beacham GM, Partlow EA, Lange JJ, Hollopeter G (January 2018). "NECAPs are negative regulators of the AP2 clathrin adaptor complex". eLife. 7: e32242. doi: 10.7554/eLife.32242 . PMC   5785209 . PMID   29345618.
  4. 1 2 3 Kirchhausen T, Owen D, Harrison SC (May 2014). "Molecular structure, function, and dynamics of clathrin-mediated membrane traffic". Cold Spring Harbor Perspectives in Biology. 6 (5): a016725. doi:10.1101/cshperspect.a016725. PMC   3996469 . PMID   24789820.
  5. ↑ Partlow EA, Baker RW, Beacham GM, Chappie JS, Leschziner AE, Hollopeter G (August 2019). "A structural mechanism for phosphorylation-dependent inactivation of the AP2 complex". eLife. 8: e50003. doi: 10.7554/eLife.50003 . PMC   6739873 . PMID   31464684.
  6. 1 2 Beacham GM, Partlow EA, Hollopeter G (October 2019). "Conformational regulation of AP1 and AP2 clathrin adaptor complexes". Traffic. 20 (10): 741–751. doi:10.1111/tra.12677. PMC   6774827 . PMID   31313456.
  7. ↑ Ehrlich M, Boll W, Van Oijen A, Hariharan R, Chandran K, Nibert ML, Kirchhausen T (September 2004). "Endocytosis by random initiation and stabilization of clathrin-coated pits". Cell. 118 (5): 591–605. doi: 10.1016/j.cell.2004.08.017 . PMID   15339664.
  8. ↑ Rapoport I, Miyazaki M, Boll W, Duckworth B, Cantley LC, Shoelson S, Kirchhausen T (May 1997). "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. PMC   1169826 . PMID   9171339.
  9. 1 2 Kadlecova Z, Spielman SJ, Loerke D, Mohanakrishnan A, Reed DK, Schmid SL (January 2017). "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. PMC   5223608 . PMID   28003333.
  10. ↑ Reider A, Barker SL, Mishra SK, Im YJ, Maldonado-Báez L, Hurley JH, et al. (October 2009). "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. PMC   2771086 . PMID   19713939.
  11. ↑ Henne WM, Boucrot E, Meinecke M, Evergren E, Vallis Y, Mittal R, McMahon HT (June 2010). "FCHo proteins are nucleators of clathrin-mediated endocytosis". Science. 328 (5983): 1281–1284. doi:10.1126/science.1188462. PMC   2883440 . PMID   20448150.
  12. ↑ Cocucci E, Aguet F, Boulant S, Kirchhausen T (August 2012). "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. PMC   3413093 . PMID   22863004.
  13. ↑ Ghosh P, Kornfeld S (March 2003). "AP-1 binding to sorting signals and release from clathrin-coated vesicles is regulated by phosphorylation". The Journal of Cell Biology. 160 (5): 699–708. doi: 10.1083/jcb.200211080 . PMC   2173368 . PMID   12604586.
  14. ↑ Ricotta D, Conner SD, Schmid SL, von Figura K, Honing S (March 2002). "Phosphorylation of the AP2 mu subunit by AAK1 mediates high affinity binding to membrane protein sorting signals". The Journal of Cell Biology. 156 (5): 791–795. doi:10.1083/jcb.200111068. PMC   2173304 . PMID   11877457.
  15. 1 2 Tian Y, Chang JC, Fan EY, Flajolet M, Greengard P (October 2013). "Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer's APP-CTF for terminal degradation via autophagy". Proceedings of the National Academy of Sciences of the United States of America. 110 (42): 17071–17076. doi: 10.1073/pnas.1315110110 . PMC   3801056 . PMID   24067654.
  16. ↑ Dhingra A, Alexander D, Reyes-Reveles J, Sharp R, Boesze-Battaglia K (2018). "Microtubule-Associated Protein 1 Light Chain 3 (LC3) Isoforms in RPE and Retina". Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology. Vol. 1074. pp. 609–616. doi:10.1007/978-3-319-75402-4_74. ISBN   978-3-319-75401-7. PMID   29721994.
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