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 We have recently determined the structure of a core domain in Bud6 that binds to Bni1 (unpublished).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.
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