Thursday, January 2, 2025
1/2/2025
Project Summary/Abstract Regulated shedding of membrane protein ectodomains is a strategy cells utilize to control the abundance or activity of membrane proteins. This “ectodomain shedding” is catalyzed by a diverse set of extracellular and transmembrane metalloproteases which includes the single pass transmembrane zinc metalloprotease A disintegrin and metalloprotease 10 (ADAM10). ADAM10 is essential for critical signaling pathways including the Notch and Epidermal Growth Factor Receptor pathways, and it is an important regulator of cell-cell contacts through its activity on cadherins. ADAM10 is the primary α-secretase responsible for the non-amyloidogenic cleavage of amyloid precursor protein (APP), and its dysfunction is implicated in numerous pathologies including neurodegenerative diseases and several cancers. ADAM10 is tightly regulated by the C8 subfamily of tetraspanins (TspanC8s), which are four-pass transmembrane proteins broadly implicated in regulatory networks at the cell surface. Current evidence suggests that TspanC8s influence ADAM10 substrate selectivity, but the mechanisms that underpin this regulation are not fully understood. One recent study showed that ADAM10 binding to Tspan15 opens access to the ADAM10 active site, and that Tspan15 orients the ADAM10 active site in a fixed position relative to the membrane surface. The surface on Tspan15 responsible for positioning the ADAM10 active site is not well-conserved among TspanC8s, suggesting that differences here could contribute to differences in substrate selectivity among ADAM10-TspanC8 complexes. Studies of other ADAM10-TspanC8 complexes will begin to fill out a broader understanding of how TspanC8s regulate ADAM10. The proposed studies aim to combine structural (Aim 1) and biochemical (Aim 2) studies of an ADAM10-Tspan5 complex to understand how key structural features differ between ADAM10-TspanC8 complexes and how these features influence the function of the complex. These studies will be carried out in the Department of Biochemistry and Molecular Pharmacology at Harvard Medical School, a highly collaborative environment with robust cross- disciplinary support, and they will support the technical development of the lead investigator in areas including cryo-electron microscopy, membrane protein biochemistry, and cell culture. The results of these studies will provide key insights into how ADAM10-TspanC8 complexes differentially control ADAM10 function in health and disease and have the potential to inform the development of novel therapeutic strategies for conditions involving dysregulated proteolysis, such as cancer and neurodegeneration. The training and experience gained by the lead investigator will create a pathway for the establishment of an independent research laboratory.
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