5ms9 | pdb_00005ms9

Solution structure of Human Fibrillin-1 EGF2-EGF3-Hybrid1-cbEGF1 four domain fragment

spinqualitylabelsall models 5ms9 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ms9 is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease FBN1_HUMAN Defects in FBN1 are a cause of Marfan syndrome (MFS) [MIM:154700. MFS is an autosomal dominant disorder that affects the skeletal, ocular, and cardiovascular systems. A wide variety of skeletal abnormalities occurs with MFS, including scoliosis, chest wall deformity, tall stature, abnormal joint mobility. Ectopia lentis occurs in up to about 80% of MFS patients and is almost always bilateral. The leading cause of premature death in MFS patients is progressive dilation of the aortic root and ascending aorta, causing aortic incompetence and dissection. Note=The majority of the more than 600 mutations in FBN1 currently known are point mutations, the rest are frameshifts and splice site mutations. Marfan syndrome has been suggested in at least 2 historical figures, Abraham Lincoln and Paganini. Defects in FBN1 are a cause of ectopia lentis, isolated, autosomal dominant (ECTOL1) [MIM:129600. An ocular abnormality characterized by partial or complete displacement of the lens from its space resulting from defective zonule formation. Defects in FBN1 are the cause of Weill-Marchesani syndrome 2 (WMS2) [MIM:608328. A rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and eye abnormalities including microspherophakia, ectopia lentis, severe myopia and glaucoma. Defects in FBN1 are a cause of Shprintzen-Goldberg craniosynostosis syndrome (SGS) [MIM:182212. SGS is a very rare syndrome characterized by a marfanoid habitus, craniosynostosis, characteristic dysmorphic facial features, skeletal and cardiovascular abnormalities, mental retardation, developmental delay and learning disabilities.[:] Defects in FBN1 are a cause of overlap connective tissue disease (OCTD) [MIM:604308. A heritable disorder of connective tissue characterized by involvement of the mitral valve, aorta, skeleton, and skin. MASS syndrome is closely resembling both the Marfan syndrome and the Barlow syndrome. However, no dislocation of the lenses or aneurysmal changes occur in the aorta, and the mitral valve prolapse is by no means invariable. Defects in FBN1 are a cause of stiff skin syndrome (SSKS) [MIM:184900. It is a syndrome characterized by hard, thick skin, usually over the entire body, which limits joint mobility and causes flexion contractures. Other occasional findings include lipodystrophy and muscle weakness. Defects in FBN1 are the cause of geleophysic dysplasia type 2 (GPHYSD2) [MIM:614185. An autosomal dominant disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have characteristic facial features including a 'happy' face with full cheeks, shortened nose, hypertelorism, long and flat philtrum, and thin upper lip. Other distinctive features include progressive cardiac valvular thickening often leading to an early death, toe walking, tracheal stenosis, respiratory insufficiency, and lysosomal-like storage vacuoles in various tissues. Defects in FBN1 are the cause of acromicric dysplasia (ACMICD) [MIM:102370. An autosomal dominant disorder characterized by severe short stature, short hands and feet, joint limitations, and skin thickening. Radiologic features include delayed bone age, cone-shaped epiphyses, shortened long tubular bones, and ovoid vertebral bodies. Affected individuals have distinct facial features, including round face, well-defined eyebrows, long eyelashes, bulbous nose with anteverted nostrils, long and prominent philtrum, and thick lips with a small mouth. Other characteristic features include hoarse voice and pseudomuscular build, and there are distinct skeletal features as well, including an internal notch of the femoral head, internal notch of the second metacarpal, and external notch of the fifth metacarpal. Function FBN1_HUMAN Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles. Fibrillin-1-containing microfibrils provide long-term force bearing structural support. Regulates osteoblast maturation by controlling TGF-beta bioavailability and calibrating TGF-beta and BMP levels, respectively (By similarity). Publication Abstract from PubMed Fibrillin-1 (FBN1) mutations associated with Marfan syndrome lead to an increase in transforming growth factor beta (TGF-beta) activation in connective tissues resulting in pathogenic changes including aortic dilatation and dissection. Since FBN1 binds latent TGF-beta binding proteins (LTBPs), the major reservoir of TGF-beta in the extracellular matrix (ECM), we investigated the structural basis for the FBN1/LTBP1 interaction. We present the structure of a four-domain FBN1 fragment, EGF2-EGF3-Hyb1-cbEGF1 (FBN1E2cbEGF1), which reveals a near-linear domain organization. Binding studies demonstrate a bipartite interaction between a C-terminal LTBP1 fragment and FBN1E2cbEGF1, which lies adjacent to the latency-associated propeptide (LAP)/TGF-beta binding site of LTBP1. Modeling of the binding interface suggests that, rather than interacting along the longitudinal axis, LTBP1 anchors itself to FBN1 using two independent epitopes. As part of this mechanism, a flexible pivot adjacent to the FBN1/LTBP1 binding site allows LTBP1 to make contacts with different ECM networks while presumably facilitating a force-induced/traction-based TGF-beta activation mechanism. The N-Terminal Region of Fibrillin-1 Mediates a Bipartite Interaction with LTBP1.,Robertson IB, Dias HF, Osuch IH, Lowe ED, Jensen SA, Redfield C, Handford PA Structure. 2017 Aug 1;25(8):1208-1221.e5. doi: 10.1016/j.str.2017.06.003. Epub, 2017 Jun 29. PMID:28669633 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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