Integrating structural and evolutionary data to interpret variation and pathogenicity in adapter protein complex 4

Protein Sci. 2020 Jun;29(6):1535-1549. doi: 10.1002/pro.3870. Epub 2020 Apr 25.

Abstract

Genetic variation in the membrane trafficking adapter protein complex 4 (AP-4) can result in pathogenic neurological phenotypes including microencephaly, spastic paraplegias, epilepsy, and other developmental defects. We lack molecular mechanisms responsible for impaired AP-4 function arising from genetic variation, because AP-4 remains poorly understood structurally. Here, we analyze patterns of AP-4 genetic evolution and conservation to identify regions that are likely important for function and thus more susceptible to pathogenic variation. We map known variants onto an AP-4 homology model and predict the likelihood of pathogenic variation at a given location on the structure of AP-4. We find significant clustering of likely pathogenic variants located at the interface between the β4 and N-μ4 subunits, as well as throughout the C-μ4 subunit. Our work offers an integrated perspective on how genetic and evolutionary forces affect AP-4 structure and function. As more individuals with uncharacterized AP-4 variants are identified, our work provides a foundation upon which their functional effects and disease relevance can be interpreted.

Publication types

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

MeSH terms

  • Adaptor Protein Complex 4 / chemistry*
  • Adaptor Protein Complex 4 / genetics*
  • Adaptor Protein Complex 4 / metabolism
  • Evolution, Molecular
  • Genetic Variation / genetics
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Sequence Homology, Amino Acid

Substances

  • Adaptor Protein Complex 4