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1000
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Abstract/Summary
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BACKGROUND: γ-Secretase is composed of four subunits with 19 transmembrane domains. -
RESULTS: Transmembrane domain (TMD) 4 of presenilin 1 contains polar amino acids that are involved in ER retention, assembly, and stability. -
CONCLUSION: TMD4 is a crucial interaction site in the γ-secretase complex. -
SIGNIFICANCE: Understanding TMD-TMD interactions in molecular detail is crucial for understanding of γ-secretase and other membrane protein complexes
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γ-Secretase is composed of the four membrane proteins presenilin, nicastrin, Pen2, and Aph1. These four proteins assemble in a coordinated and regulated manner into a high molecular weight complex. The subunits constitute a total of 19 transmembrane domains (TMD), with many carrying important amino acids involved in catalytic activity, interaction with other subunits, or in ER retention/retrieval of unassembled subunits. We here focus on TMD4 of presenilin 1 (PS1) and show that a number of polar amino acids are critical for γ-secretase assembly and function. An asparagine, a threonine, and an aspartate form a polar interface important for endoplasmic reticulum retention/retrieval. A single asparagine in TMD4 of PS1 is involved in a protein-protein interaction by binding to another asparagine in Pen2. Intriguingly, a charged aspartate in TMD4 is critical for γ-secretase activity, most likely by stabilizing the newly formed complex.
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