Type IIB receptor protein tyrosine phosphatases are cell surface transmembrane proteins that engage in cell adhesion via their extracellular domains (ECDs) and cell signaling via their cytoplasmic phosphatase domains. The ECDs of type IIB receptor protein tyrosine phosphatases form stable, homophilic, and trans interactions between adjacent cell membranes. Previous work has demonstrated how one family member, PTPRM, forms head-to-tail homodimers. However, as the interface was composed of residues conserved across the family, the determinants of homophilic specificity remain unknown. Here, we have solved the X-ray crystal structure of the membrane-distal N-terminal domains of PTPRK that form a head-to-tail dimer consistent with intermembrane adhesion. Comparison with the PTPRM structure demonstrates interdomain conformational differences that may define homophilic specificity. Using small-angle X-ray scattering, we determined the solution structures of the full-length ECDs of PTPRM and PTPRK, identifying that both are rigid extended molecules that differ in their overall long-range conformation. Furthermore, we identified one residue, W351, within the interaction interface that differs between PTPRM and PTPRK and showed that mutation to glycine, the equivalent residue in PTPRM, abolishes PTPRK dimer formation in vitro. This comparison of two members of the receptor tyrosine phosphatase family suggests that homophilic specificity is driven by a combination of shape complementarity and specific but limited sequence differences.

IIB 型受体蛋白酪氨酸磷酸酶是细胞表面跨膜蛋白，通过其细胞外结构域 (ECD)参与细胞粘附，并通过细胞信号转导它们的细胞质磷酸酶结构域。IIB 型受体蛋白酪氨酸磷酸酶的 ECD 在相邻细胞膜之间形成稳定、嗜同和反式相互作用。以前的工作已经证明了一个家庭成员 PTPRM 如何形成头尾同源二聚体。然而，由于界面由整个家族保守的残基组成，嗜同特异性的决定因素仍然未知。在这里，我们已经解决了 PTPRK 的膜远端 N 末端结构域的 X 射线晶体结构，该结构域形成与膜间粘附一致的头尾二聚体。与 PTPRM 结构的比较表明域间构象差异可能定义嗜同特异性。使用小角度 X 射线散射，我们确定了 PTPRM 和 PTPRK 的全长 ECD 的溶液结构，确定两者都是刚性扩展分子，它们的整体远程构象不同。此外，我们在 PTPRM 和 PTPRK 之间的相互作用界面内鉴定了一个残基 W351，并表明突变为甘氨酸（PTPRM 中的等效残基）消除了 PTPRK 二聚体形成体外。受体酪氨酸磷酸酶家族的两个成员的这种比较表明，嗜同特异性是由形状互补性和特定但有限的序列差异的组合驱动的。