6anu

Cryo-EM structure of F-actin complexed with the beta-III-spectrin actin-binding domain

Loading... Status: waiting for Mol* initialization Structural highlights 6anu is a 12 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Gene: ACTB (HUMAN), SPTBN2, KIAA0302, SCA5 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [ACTB_HUMAN] Defects in ACTB are a cause of dystonia juvenile-onset (DYTJ) [MIM:607371]. DYTJ is a form of dystonia with juvenile onset. Dystonia is defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYTJ patients manifest progressive, generalized, dopa-unresponsive dystonia, developmental malformations and sensory hearing loss. Defects in ACTB are the cause of Baraitser-Winter syndrome type 1 (BRWS1) [MIM:243310]. A rare developmental disorder characterized by the combination of congenital ptosis, high-arched eyebrows, hypertelorism, ocular colobomata, and a brain malformation consisting of anterior-predominant lissencephaly. Other typical features include postnatal short stature and microcephaly, intellectual disability, seizures, and hearing loss. [SPTN2_HUMAN] Defects in SPTBN2 are the cause of spinocerebellar ataxia type 5 (SCA5) [MIM:600224]. Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA5 is an autosomal dominant cerebellar ataxia (ADCA). It is a slowly progressive disorder with variable age at onset, ranging between 10 and 50 years. Function [ACTB_HUMAN] Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells. [SPTN2_HUMAN] Probably plays an important role in neuronal membrane skeleton. Publication Abstract from PubMed Spinocerebellar ataxia type 5 (SCA5) is a neurodegenerative disease caused by mutations in the cytoskeletal protein beta-III-spectrin. Previously, a SCA5 mutation resulting in a leucine-to-proline substitution (L253P) in the actin-binding domain (ABD) was shown to cause a 1000-fold increase in actin-binding affinity. However, the structural basis for this increase is unknown. Here, we report a 6.9 A cryo-EM structure of F-actin complexed with the L253P ABD. This structure, along with co-sedimentation and pulsed-EPR measurements, demonstrates that high-affinity binding caused by the CH2-localized mutation is due to opening of the two CH domains. This enables CH1 to bind actin aided by an unstructured N-terminal region that becomes alpha-helical upon binding. This helix is required for association with actin as truncation eliminates binding. Collectively, these results shed light on the mechanism by which beta-III-spectrin, and likely similar actin-binding proteins, interact with actin, and how this mechanism can be perturbed to cause disease. Structural basis for high-affinity actin binding revealed by a beta-III-spectrin SCA5 missense mutation.,Avery AW, Fealey ME, Wang F, Orlova A, Thompson AR, Thomas DD, Hays TS, Egelman EH Nat Commun. 2017 Nov 7;8(1):1350. doi: 10.1038/s41467-017-01367-w. PMID:29116080 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Actin 3D structures Spectrin

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