WNK1 is an assembly factor for the human ER membrane protein complex

Mol Cell. 2021 Jul 1;81(13):2693-2704.e12. doi: 10.1016/j.molcel.2021.04.013. Epub 2021 May 7.

Abstract

The assembly of nascent proteins into multi-subunit complexes is a tightly regulated process that must occur at high fidelity to maintain cellular homeostasis. The ER membrane protein complex (EMC) is an essential insertase that requires seven membrane-spanning and two soluble cytosolic subunits to function. Here, we show that the kinase with no lysine 1 (WNK1), known for its role in hypertension and neuropathy, functions as an assembly factor for the human EMC. WNK1 uses a conserved amphipathic helix to stabilize the soluble subunit, EMC2, by binding to the EMC2-8 interface. Shielding this hydrophobic surface prevents promiscuous interactions of unassembled EMC2 and directly competes for binding of E3 ubiquitin ligases, permitting assembly. Depletion of WNK1 thus destabilizes both the EMC and its membrane protein clients. This work describes an unexpected role for WNK1 in protein biogenesis and defines the general requirements of an assembly factor that will apply across the proteome.

Keywords: amphipathic helix; assembly factor; hydrophobic interface; kinase; membrane protein; protein biogenesis; protein complex assembly; protein quality control; ubiquitination.

Publication types

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

MeSH terms

  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • HeLa Cells
  • Humans
  • Intracellular Membranes / metabolism*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • WNK Lysine-Deficient Protein Kinase 1 / genetics
  • WNK Lysine-Deficient Protein Kinase 1 / metabolism*

Substances

  • Multiprotein Complexes
  • WNK Lysine-Deficient Protein Kinase 1
  • WNK1 protein, human