AAGAB Controls AP2 Adaptor Assembly in Clathrin-Mediated Endocytosis

Dev Cell. 2019 Aug 19;50(4):436-446.e5. doi: 10.1016/j.devcel.2019.06.013. Epub 2019 Jul 25.


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.

Keywords: AP1 adaptor; AP2 adaptor; CRISPR screen; adaptor complex; clathrin-mediated endocytosis; membrane trafficking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 2 / genetics*
  • Adaptor Proteins, Vesicular Transport / genetics*
  • Amino Acid Sequence / genetics
  • Cell Membrane / genetics
  • Clathrin / genetics
  • Endocytosis / genetics*
  • Humans
  • Keratoderma, Palmoplantar / genetics
  • Keratoderma, Palmoplantar / pathology
  • Protein Binding / genetics
  • Protein Transport / genetics
  • Proteolysis


  • AAGAB protein, human
  • Adaptor Protein Complex 2
  • Adaptor Proteins, Vesicular Transport
  • Clathrin