Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio, United States of America.
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio, United States of America.
PLoS Biol. 2021 Dec 6;19(12):e3001463. doi: 10.1371/journal.pbio.3001463. eCollection 2021 Dec.
Enterocytes are specialized epithelial cells lining the luminal surface of the small intestine that build densely packed arrays of microvilli known as brush borders. These microvilli drive nutrient absorption and are arranged in a hexagonal pattern maintained by intermicrovillar links formed by 2 nonclassical members of the cadherin superfamily of calcium-dependent cell adhesion proteins: protocadherin-24 (PCDH24, also known as CDHR2) and the mucin-like protocadherin (CDHR5). The extracellular domains of these proteins are involved in heterophilic and homophilic interactions important for intermicrovillar function, yet the structural determinants of these interactions remain unresolved. Here, we present X-ray crystal structures of the PCDH24 and CDHR5 extracellular tips and analyze their species-specific features relevant for adhesive interactions. In parallel, we use binding assays to identify the PCDH24 and CDHR5 domains involved in both heterophilic and homophilic adhesion for human and mouse proteins. Our results suggest that homophilic and heterophilic interactions involving PCDH24 and CDHR5 are species dependent with unique and distinct minimal adhesive units.
肠上皮细胞是一种特化的上皮细胞，排列在小肠的腔面，形成被称为刷状缘的紧密微绒毛排列。这些微绒毛推动营养物质吸收，并通过由钙依赖性细胞黏附蛋白家族的 2 个非经典成员形成的细胞间微绒毛连接来维持六边形模式：原钙黏蛋白-24（protocadherin-24，也称为 CDHR2）和黏蛋白样原钙黏蛋白（protocadherin-5，CDHR5）。这些蛋白的细胞外结构域参与同种异型和同种异型相互作用，对于细胞间微绒毛功能至关重要，但这些相互作用的结构决定因素仍未解决。在这里，我们展示了 PCDH24 和 CDHR5 细胞外尖端的 X 射线晶体结构，并分析了与其黏附相互作用相关的种特异性特征。同时，我们使用结合测定法鉴定了人源和鼠源蛋白中涉及同种异型和同种异型黏附的 PCDH24 和 CDHR5 结构域。我们的结果表明，涉及 PCDH24 和 CDHR5 的同种异型和异质型相互作用具有种属依赖性，具有独特而不同的最小黏附单位。
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