8fg1 | pdb_00008fg1
Human diaphanous inhibitory domain bound to diaphanous autoregulatory domain
Structural highlights
DiseaseDIAP1_HUMAN Moyamoya disease;DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome;Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionDIAP1_HUMAN Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers (By similarity). Binds to the barbed end of the actin filament and slows down actin polymerization and depolymerization (By similarity). Required for cytokinesis, and transcriptional activation of the serum response factor (By similarity). DFR proteins couple Rho and Src tyrosine kinase during signaling and the regulation of actin dynamics (By similarity). Functions as a scaffold protein for MAPRE1 and APC to stabilize microtubules and promote cell migration (By similarity). Has neurite outgrowth promoting activity. Acts in a Rho-dependent manner to recruit PFY1 to the membrane (By similarity). In hear cells, it may play a role in the regulation of actin polymerization in hair cells (PubMed:20937854, PubMed:21834987, PubMed:26912466). The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854, PubMed:21834987). It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity (PubMed:20937854, PubMed:21834987). In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (PubMed:20937854, PubMed:21834987). Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape (PubMed:20937854, PubMed:21834987). Plays a role in brain development (PubMed:24781755). Also acts as an actin nucleation and elongation factor in the nucleus by promoting nuclear actin polymerization inside the nucleus to drive serum-dependent SRF-MRTFA activity (By similarity).[UniProtKB:O08808][1] [2] [3] [4] Publication Abstract from PubMedThe diaphanous-related-formin, Diaphanous 1 (DIAPH1), is required for the assembly of Filamentous (F)-actin structures. DIAPH1 is an intracellular effector of the receptor for advanced glycation end products (RAGE) and contributes to RAGE signaling and effects such as increased cell migration upon RAGE stimulation. Mutations in DIAPH1, including those in the basic "RRKR" motif of its autoregulatory domain, diaphanous autoinhibitory domain (DAD), are implicated in hearing loss, macrothrombocytopenia and cardiovascular diseases. The solution structure of the complex between the N-terminal inhibitory domain, DID, and the C-terminal DAD, resolved by NMR spectroscopy shows only transient interactions between DID and the basic motif of DAD, resembling those found in encounter complexes. Cross-linking studies placed the RRKR motif into the negatively charged cavity of DID. Neutralizing the cavity resulted in a five-fold decrease in the binding affinity and four-fold decrease in the association rate constant of DAD for DID, indicating that the RRKR interactions with DID form a productive encounter complex. A DIAPH1 mutant containing a neutralized RRKR binding cavity shows excessive co-localization with actin and is unresponsive to RAGE stimulation. This is the first demonstration of a specific alteration of the surfaces responsible for productive encounter complexation with implications for human pathology. Disruption of the Productive Encounter Complex Results in Dysregulation of DIAPH1 Activity.,Theophall GG, Ramirez LMS, Premo A, Reverdatto S, Manigrasso MB, Yepuri G, Burz DS, Ramasamy R, Schmidt AM, Shekhtman A J Biol Chem. 2023 Oct 11:105342. doi: 10.1016/j.jbc.2023.105342. PMID:37832872[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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