CRYSTAL STRUCTURE OF A COILED COIL DOMAIN OF HUMAN P160ROCK

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 形成蛋白是参与广泛的细胞骨架过程的多结构域蛋白。 它们是所有真核生物中细胞极性、细胞迁移、胞质分裂和形态发生所必需的。 肌动蛋白的定义特征是形成蛋白同源性2（FH 2）结构域，其直接使肌动蛋白丝成核，并且在其生长时保持与丝的倒刺末端的前连接。 为了更好地了解formins如何在特定的细胞环境中发挥作用，我们正在研究一种遗传和生物化学上经过充分验证的酵母伴侣蛋白，即酵母蛋白Bud 6。 Bud 6在酵母中是一个关键的结合伴侣和调节子。 我们最近确定了Bud 6中与Bni 1结合的核心结构域的结构（未发表）。 Bud 6没有已知的人类同源物。 然而，根据结构，重新检查Bud 6的该区域与哺乳动物蛋白ROCK 1之间的一级序列的弱相似性，表明序列相似性反映了这两种蛋白质中共有的结构和可能的功能特征。 ROCK（Rho相关激酶）是Rho依赖性信号传导的效应子，介导应力纤维和粘着斑形成。 它还参与许多其他细胞过程，包括平滑肌收缩、细胞迁移和神经突生长。 Rho-ROCK通路的异常激活在肿瘤侵袭转移、高血压和支气管哮喘中发挥作用。 Bud 6和人ROCK 1的肌动蛋白结合域之间的结构和功能平行，如果被证明是正确的，将是一个突破性的发现。 它们相似的结构可以成为药物开发的目标。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Formins are multidomain proteins that participate in a wide range of cytoskeletal processes. They are required for cell polarity, cell migration, cytokinesis, and morphogenesis in all eukaryotes. The defining feature of formin proteins is the Formin Homology 2 (FH2) domain, which directly nucleates actin filaments and remains processively associated with the barbed end of the filament as it grows. To better understand how formins work in specific cellular contexts, we are studying a genetically and biochemically well-validated formin partner protein, the yeast protein Bud6. Bud6 is a key binding partner and regulator of the formin Bni1 in yeast. We have recently determined the structure of a core domain in Bud6 that binds to Bni1 (unpublished). Bud6 has no known human homologs. However, re-examination of a weak similarity in primary sequence between this region of Bud6 and the mammalian protein ROCK1, in light of the structure, suggests that the sequence similarity is reflective of a shared structural and perhaps functional feature in these two proteins. ROCK (Rho-associated kinase) is an effector of Rho-dependent signaling to mediate stress fibers and focal adhesion formation. It is also involved in many other cellular processes including smooth muscle contraction, cell migration, and neurite outgrowth. Abnormal activation of the Rho-ROCK pathway plays role in tumor invasion and metastasis, hypertension, and bronchial asthma. A structural and functional parallel between the actin binding domains of Bud6 and human ROCK1 if proven correct will be a breakthrough finding. Their similar structures can be a target for drug development.