Structure of human SNX10 reveals insights into its role in human autosomal recessive osteopetrosis

Proteins. 2014 Dec;82(12):3483-9. doi: 10.1002/prot.24689. Epub 2014 Oct 1.

Abstract

Sorting nexin 10 (SNX10), the unique member of the SNX family having vacuolation activity in cells, was shown to be involved in the development of autosomal recessive osteopetrosis (ARO) in recent genetic studies. However, the molecular mechanism of the disease-related mutations affecting the biological function of SNX10 is unclear. Here, we report the crystal structure of human SNX10 to 2.6 Å resolution. The structure reveals that SNX10 contains the extended phox-homology domain we previously proposed. Our study provides the structural details of those disease-related mutations. Combined with the vacuolation study of those mutations, we found that Tyr32 and Arg51 are important for the protein stability and both play a critical role in vacuolation activity, while Arg16Leu may affect the function of SNX10 in osteoclast through protein-protein interactions.

Keywords: PXe domain; SNX10; endosome homeostasis; osteopetrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Arginine / chemistry
  • Humans
  • MCF-7 Cells
  • Models, Molecular*
  • Molecular Sequence Data
  • Mutation*
  • Osteoclasts / metabolism
  • Osteopetrosis / congenital*
  • Osteopetrosis / genetics
  • Osteopetrosis / metabolism
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Protein Stability
  • Protein Structure, Tertiary
  • Protein Transport
  • Recombinant Proteins / chemistry
  • Sequence Alignment
  • Sorting Nexins / chemistry*
  • Sorting Nexins / genetics
  • Sorting Nexins / metabolism
  • Tyrosine / chemistry
  • Vacuoles / metabolism

Substances

  • Recombinant Proteins
  • SNX10 protein, human
  • Sorting Nexins
  • Tyrosine
  • Arginine

Associated data

  • PDB/4ON3
  • PDB/4PZG