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Crystal structure of the Tspan15 LEL domain reveals a conserved ADAM10 binding site.

Lipper CH, Gabriel KH, Seegar TCM, Dürr KL, Tomlinson MG, Blacklow SC
Structure 30 206-214.e4 (2022)
Cited: 9 times
EuropePMC logo PMID: 34739841

Abstract

Tetraspanins are four-pass transmembrane proteins that function by regulating trafficking of partner proteins and organizing signaling complexes in the membrane. Tspan15, one of a six-member TspanC8 subfamily, forms a complex that regulates the trafficking, maturation, and substrate selectivity of the transmembrane protease ADAM10, an essential enzyme in mammalian physiology that cleaves a wide variety of membrane-anchored substrates, including Notch receptors, amyloid precursor protein, cadherins, and growth factors. We present here crystal structures of the Tspan15 large extracellular loop (LEL) required for functional association with ADAM10 both in isolation and in complex with the Fab fragment of an anti-Tspan15 antibody. Comparison of the Tspan15 LEL with other tetraspanin LEL structures shows that a core helical framework buttresses a variable region that structurally diverges among LELs. Using co-immunoprecipitation and a cellular N-cadherin cleavage assay, we identify a site on Tspan15 required for both ADAM10 binding and promoting substrate cleavage.

Articles - 7rd5 mentioned but not cited (2)

  1. Structural basis for membrane-proximal proteolysis of substrates by ADAM10. Lipper CH, Egan ED, Gabriel KH, Blacklow SC. Cell 186 3632-3641.e10 (2023)
  2. Crystal structure of the Tspan15 LEL domain reveals a conserved ADAM10 binding site. Lipper CH, Gabriel KH, Seegar TCM, Dürr KL, Tomlinson MG, Blacklow SC. Structure 30 206-214.e4 (2022)


Reviews citing this publication (3)

  1. Tetraspanins: structure, dynamics, and principles of partner-protein recognition. Susa KJ, Kruse AC, Blacklow SC. Trends Cell Biol 34 509-522 (2024)
  2. Inducing prion protein shedding as a neuroprotective and regenerative approach in pathological conditions of the brain: from theory to facts. Matamoros-Angles A, Mohammadi B, Song F, Shafiq M, Brenna S, Puig B, Glatzel M, Altmeppen HC. Neural Regen Res 18 1869-1875 (2023)
  3. ADAM10-a "multitasker" in sepsis: focus on its posttranslational target. Liao S, Lin Y, Liu L, Yang S, Lin Y, He J, Shao Y. Inflamm Res 72 395-423 (2023)

Articles citing this publication (4)

  1. The Platelet Collagen Receptor GPVI Is Cleaved by Tspan15/ADAM10 and Tspan33/ADAM10 Molecular Scissors. Koo CZ, Matthews AL, Harrison N, Szyroka J, Nieswandt B, Gardiner EE, Poulter NS, Tomlinson MG. Int J Mol Sci 23 2440 (2022)
  2. CD9 co-operation with syndecan-1 is required for a major staphylococcal adhesion pathway. Green LR, Issa R, Albaldi F, Urwin L, Thompson R, Khalid H, Turner CE, Ciani B, Partridge LJ, Monk PN. mBio 14 e0148223 (2023)
  3. Comparative study of PRPH2 D2 loop mutants reveals divergent disease mechanism in rods and cones. Ikelle L, Makia M, Lewis T, Crane R, Kakakhel M, Conley SM, Birtley JR, Arshavsky VY, Al-Ubaidi MR, Naash MI. Cell Mol Life Sci 80 214 (2023)
  4. A molecular docking exploration of the large extracellular loop of tetraspanin CD81 with small molecules. Bailly C, Bedart C, Vergoten G. In Silico Pharmacol 12 24 (2024)


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