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

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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.

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Gadbery, J. E., Abraham, A., Needle, C. D., Moth, C., Sheehan, J., Capra, J. A., & Jackson, L. P. (2020). Integrating structural and evolutionary data to interpret variation and pathogenicity in adapter protein complex 4. Protein Science, 29(6), 1535–1549. https://doi.org/10.1002/pro.3870

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