AAGAB Controls AP2 Adaptor Assembly in Clathrin-Mediated Endocytosis

• Published in: Developmental cell Vol. 50; no. 4; pp. 436 - 446.e5
• Main Authors: Gulbranson, Daniel R., Crisman, Lauren, Lee, MyeongSeon, Ouyang, Yan, Menasche, Bridget L., Demmitt, Brittany A., Wan, Chun, Nomura, Toshifumi, Ye, Yihong, Yu, Haijia, Shen, Jingshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.08.2019
• Subjects: adaptor complex; Adaptor Protein Complex 2 - genetics; Adaptor Proteins, Vesicular Transport - genetics; Amino Acid Sequence - genetics; AP1 adaptor; AP2 adaptor; Cell Membrane - genetics; Clathrin - genetics; clathrin-mediated endocytosis; CRISPR screen; Endocytosis - genetics; Humans; Keratoderma, Palmoplantar - genetics; Keratoderma, Palmoplantar - pathology; membrane trafficking; Protein Binding - genetics; Protein Transport - genetics; Proteolysis; CRISPR screen; AP2 adaptor; adaptor complex; membrane trafficking; AP1 adaptor; clathrin-mediated endocytosis
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2019.06.013

Multimeric adaptors are broadly involved in vesicle-mediated membrane trafficking. AP2 adaptor, in particular, plays a central role in clathrin-mediated endocytosis (CME) by recruiting cargo and clathrin to endocytic sites. It is generally thought that trafficking adaptors such as AP2 adaptor assemble spontaneously. In this work, however, we discovered that AP2 adaptor assembly is an ordered process controlled by alpha and gamma adaptin binding protein (AAGAB), an uncharacterized factor identified in our genome-wide genetic screen of CME. AAGAB guides the sequential association of AP2 subunits and stabilizes assembly intermediates. Without the assistance of AAGAB, AP2 subunits fail to form the adaptor complex, leading to their degradation. The function of AAGAB is abrogated by a mutation that causes punctate palmoplantar keratoderma type 1 (PPKP1), a human skin disease. Since other multimeric trafficking adaptors operate in an analogous manner to AP2 adaptor, their assembly likely involves a similar regulatory mechanism. •AAGAB binds to the AP2 complex and is essential for clathrin-mediated endocytosis•AAGAB controls the sequential assembly of the AP2 adaptor complex•AAGAB stabilizes AP2 complex intermediates•A skin disease-causing mutation impairs the function of AAGAB The AP2 complex is required for clathrin-mediated endocytosis. Gulbranson et al. identify AAGAB as a regulator of AP2 adaptor assembly, which guides the sequential association of AP2 subunits and stabilizes assembly intermediates. The function of AAGAB is disrupted by a mutation that causes punctate palmoplantar keratoderma type 1.