2mtp
From Proteopedia
The structure of Filamin repeat 21 bound to integrin
Structural highlights
DiseaseFLNA_HUMAN Defects in FLNA are the cause of periventricular nodular heterotopia type 1 (PVNH1) [MIM:300049; also called nodular heterotopia, bilateral periventricular (NHBP or BPNH). PVNH is a developmental disorder characterized by the presence of periventricular nodules of cerebral gray matter, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. PVNH1 is an X-linked dominant form. Heterozygous females have normal intelligence but suffer from seizures and various manifestations outside the central nervous system, especially related to the vascular system. Hemizygous affected males die in the prenatal or perinatal period.[1] [2] [3] [4] [5] Defects in FLNA are the cause of periventricular nodular heterotopia type 4 (PVNH4) [MIM:300537; also known as periventricular heterotopia Ehlers-Danlos variant. PVNH4 is characterized by nodular brain heterotopia, joint hypermobility and development of aortic dilation in early adulthood. Defects in FLNA are the cause of otopalatodigital syndrome type 1 (OPD1) [MIM:311300. OPD1 is an X-linked dominant multiple congenital anomalies disease mainly characterized by a generalized skeletal dysplasia, mild mental retardation, hearing loss, cleft palate, and typical facial anomalies. OPD1 belongs to a group of X-linked skeletal dysplasias known as oto-palato-digital syndrome spectrum disorders that also include OPD2, Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. FLNA is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. Males with OPD1 have cleft palate, malformations of the ossicles causing deafness and milder bone and limb defects than those associated with OPD2. Obligate female carriers of mutations causing both OPD1 and OPD2 have variable (often milder) expression of a similar phenotypic spectrum.[6] [7] Defects in FLNA are the cause of otopalatodigital syndrome type 2 (OPD2) [MIM:304120; also known as cranioorodigital syndrome. OPD2 is a congenital bone disorder that is characterized by abnormally modeled, bowed bones, small or absent first digits and, more variably, cleft palate, posterior fossa brain anomalies, omphalocele and cardiac defects. Defects in FLNA are the cause of frontometaphyseal dysplasia (FMD) [MIM:305620. FMD is a congenital bone disease characterized by supraorbital hyperostosis, deafness and digital anomalies.[8] [9] Defects in FLNA are the cause of Melnick-Needles syndrome (MNS) [MIM:309350. MNS is a severe congenital bone disorder characterized by typical facies (exophthalmos, full cheeks, micrognathia and malalignment of teeth), flaring of the metaphyses of long bones, s-like curvature of bones of legs, irregular constrictions in the ribs, and sclerosis of base of skull.[10] Defects in FLNA are the cause of X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX) [MIM:300048. CIIPX is characterized by a severe abnormality of gastrointestinal motility due to primary qualitative defects of enteric ganglia and nerve fibers. Affected individuals manifest recurrent signs of intestinal obstruction in the absence of any mechanical lesion.[11] Defects in FLNA are the cause of FG syndrome type 2 (FGS2) [MIM:300321. FG syndrome (FGS) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation.[12] Defects in FLNA are the cause of terminal osseous dysplasia (TOD) [MIM:300244. A rare X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin and recurrent digital fibroma during infancy. A significant phenotypic variability is observed in affected females.[13] Defects in FLNA are the cause of cardiac valvular dysplasia X-linked (CVDX) [MIM:314400. A rare X-linked heart disease characterized by mitral and/or aortic valve regurgitation. The histologic features include fragmentation of collagenous bundles within the valve fibrosa and accumulation of proteoglycans, which produces excessive valve tissue leading to billowing of the valve leaflets.[14] Note=Defects in FLNA may be a cause of macrothrombocytopenia, a disorder characterized by subnormal levels of blood platelets. Blood platelets are abonormally enlarged. FunctionFLNA_HUMAN Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. Anchors various transmembrane proteins to the actin cytoskeleton and serves as a scaffold for a wide range of cytoplasmic signaling proteins. Interaction with FLNA may allow neuroblast migration from the ventricular zone into the cortical plate. Tethers cell surface-localized furin, modulates its rate of internalization and directs its intracellular trafficking (By similarity). Involved in ciliogenesis.[15] Publication Abstract from PubMedActivation of heterodimeric (alphabeta) integrin is crucial for regulating cell adhesion. Binding of talin to the cytoplasmic face of integrin activates the receptor, but how integrin is maintained in a resting state to counterbalance its activation has remained obscure. Here, we report the structure of the cytoplasmic domain of human integrin alphaIIbbeta3 bound to its inhibitor, the immunoglobin repeat 21 of filamin A (FLNa-Ig21). The structure reveals an unexpected ternary complex in which FLNa-Ig21 not only binds to the C terminus of the integrin beta3 cytoplasmic tail (CT), as previously predicted, but also engages N-terminal helices of alphaIIb and beta3 CTs to stabilize an inter-CT clasp that helps restrain the integrin in a resting state. Combined with functional data, the structure reveals a new mechanism of filamin-mediated retention of inactive integrin, suggesting a new framework for understanding regulation of integrin activation and adhesion. Structural mechanism of integrin inactivation by filamin.,Liu J, Das M, Yang J, Ithychanda SS, Yakubenko VP, Plow EF, Qin J Nat Struct Mol Biol. 2015 May;22(5):383-9. doi: 10.1038/nsmb.2999. Epub 2015 Apr , 6. PMID:25849143[16] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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