Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
Exp Biol Med (Maywood). 2019 Dec;244(17):1510-1519. doi: 10.1177/1535370219865901. Epub 2019 Jul 23.
ADAM (a disintegrin and metalloproteinase) proteins are type-1 transmembrane and secreted proteins that function in cell adhesion and signal transduction. Here we review the structural features of ADAM proteins that direct their biological functions in ectodomain shedding and cell adhesion.
Recent structural advances have provided a deeper appreciation for interdomain relationships that modulate the activity of ADAM proteins in ectodomain shedding and cellular adhesion. Our review covers these new findings, and places them into historical context. The new results make clear that the metalloproteinase domain works in combination with its ancillary domains to execute its biological function. The ADAM ectodomain is dynamic, and accesses conformations that require interdomain movements during its enzymatic “lifecycle.” Fundamental questions about ADAM activation and substrate selection, however, still remain unanswered. Elucidating the biochemical and structural basis for ADAM regulation will be an exciting avenue of future research that should greatly advance our understanding of ADAM function in biology and human pathogenesis.
ADAM（解整合素和金属蛋白酶）蛋白是 1 型跨膜和分泌蛋白，在细胞黏附和信号转导中发挥作用。本文综述 ADAM 蛋白的结构特征，这些结构特征指导其在细胞外结构域脱落和细胞黏附中的生物学功能。
最近的结构进展使人们更深入地了解调节 ADAM 蛋白在细胞外结构域脱落和细胞黏附中活性的域间关系。本文综述涵盖了这些新发现，并将其置于历史背景中。新结果表明，金属蛋白酶结构域与辅助结构域协同作用执行其生物学功能。ADAM 细胞外结构域是动态的，并在其酶“生命周期”中获取需要域间运动的构象。然而，关于 ADAM 激活和底物选择的基本问题仍未得到解答。阐明 ADAM 调节的生化和结构基础将是未来研究的一个令人兴奋的方向，这将极大地促进我们对 ADAM 在生物学和人类发病机制中的功能的理解。
