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Oligomer-to-monomer transition underlies the chaperone function of AAGAB in AP1/AP2 assembly.

Yuan TianIshara DattaRui YangChun WanBing WangLauren CrismanHuan HeChad A BrautigamSuzhao LiJingshi ShenQian Yin
Published in: Proceedings of the National Academy of Sciences of the United States of America (2023)
Assembly of protein complexes is facilitated by assembly chaperones. Alpha and gamma adaptin-binding protein (AAGAB) is a chaperone governing the assembly of the heterotetrameric adaptor complexes 1 and 2 (AP1 and AP2) involved in clathrin-mediated membrane trafficking. Here, we found that before AP1/2 binding, AAGAB exists as a homodimer. AAGAB dimerization is mediated by its C-terminal domain (CTD), which is critical for AAGAB stability and is missing in mutant proteins found in patients with the skin disease punctate palmoplantar keratoderma type 1 (PPKP1). We solved the crystal structure of the dimerization-mediating CTD, revealing an antiparallel dimer of bent helices. Interestingly, AAGAB uses the same CTD to recognize and stabilize the γ subunit in the AP1 complex and the α subunit in the AP2 complex, forming binary complexes containing only one copy of AAGAB. These findings demonstrate a dual role of CTD in stabilizing resting AAGAB and binding to substrates, providing a molecular explanation for disease-causing AAGAB mutations. The oligomerization state transition mechanism may also underlie the functions of other assembly chaperones.
Keyphrases
  • transcription factor
  • binding protein
  • heat shock
  • endoplasmic reticulum
  • amino acid
  • wound healing
  • protein protein