6z3g
Repulsive Guidance Molecule A (RGMA) in complex with Growth Differentiation Factor 5 (GDF5)
Structural highlights
DiseaseGDF5_HUMAN Defects in GDF5 are the cause of acromesomelic chondrodysplasia Grebe type (AMDG) [MIM:200700. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs, and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). AMDG is an autosomal recessive form characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet.[1] Defects in GDF5 are the cause of acromesomelic chondrodysplasia Hunter-Thompson type (AMDH) [MIM:201250. AMDH is an autosomal recessive form of dwarfism. Patients have limb abnormalities, with the middle and distal segments being most affected and the lower limbs more affected than the upper. AMDH is characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet. Defects in GDF5 are the cause of brachydactyly type C (BDC) [MIM:113100. BDC is an autosomal dominant disorder characterized by an abnormal shortness of the fingers and toes. Note=Some BDC patients with GDF5 mutations also manifest clinical features of ASPED angel-shaped phalango-epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. This suggests that BDC and ASPED are part of the same clinical spectrum (PubMed:22828468).[2] [3] Defects in GDF5 are the cause of Du Pan syndrome (DPS) [MIM:228900; also known as fibular hypoplasia and complex brachydactyly. Du Pan syndrome is a rare autosomal recessive condition characterized by absence of the fibulae and severe acromesomelic limb shortening with small, non-functional toes. Although milder, the phenotype resembles the autosomal recessive Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia.[4] [5] [6] Defects in GDF5 are a cause of symphalangism proximal syndrome (SYM1) [MIM:185800. SYM1 is characterized by the hereditary absence of the proximal interphalangeal (PIP) joints (Cushing symphalangism). Severity of PIP joint involvement diminishes towards the radial side. Distal interphalangeal joints are less frequently involved and metacarpophalangeal joints are rarely affected whereas carpal bone malformation and fusion are common. In the lower extremities, tarsal bone coalition is common. Conducive hearing loss is seen and is due to fusion of the stapes to the petrous part of the temporal bone.[7] [8] [9] Defects in GDF5 are the cause of multiple synostoses syndrome type 2 (SYNS2) [MIM:610017. Multiple synostoses syndrome is an autosomal dominant condition characterized by progressive joint fusions of the fingers, wrists, ankles and cervical spine, characteristic facies and progressive conductive deafness.[:][10] Defects in GDF5 are a cause of brachydactyly type A2 (BDA2) [MIM:112600. Brachydactylies (BDs) are a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. They have been classified on an anatomic and genetic basis into five groups, A to E, including three subgroups (A1 to A3) that usually manifest as autosomal dominant traits.[11] [12] Genetic variations in GDF5 are associated with susceptibility to osteoarthritis type 5 (OS5) [MIM:612400. Osteoarthritis is a degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis. Clinical symptoms include pain and joint stiffness often leading to significant disability and joint replacement. Defects in GDF5 may be a cause of brachydactyly type A1 (BDA1) [MIM:112500. Brachydactylies (BDs) are a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. They have been classified on an anatomic and genetic basis into five groups, A to E, including three subgroups (A1 to A3) that usually manifest as autosomal dominant traits.[13] FunctionGDF5_HUMAN Could be involved in bone and cartilage formation. Chondrogenic signaling is mediated by the high-affinity receptor BMPR1B.[14] [15] Publication Abstract from PubMedRepulsive guidance molecules (RGMs) are cell surface proteins that regulate the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. They control fundamental biological processes, such as migration and differentiation by direct interaction with the Neogenin (NEO1) receptor and function as coreceptors for the bone morphogenetic protein (BMP)/growth differentiation factor (GDF) family. We determined crystal structures of all three human RGM family members in complex with GDF5, as well as the ternary NEO1-RGMB-GDF5 assembly. Surprisingly, we show that all three RGMs inhibit GDF5 signaling, which is in stark contrast to RGM-mediated enhancement of signaling observed for other BMPs, like BMP2. Despite their opposite effect on GDF5 signaling, RGMs occupy the BMP type 1 receptor binding site similar to the observed interactions in RGM-BMP2 complexes. In the NEO1-RGMB-GDF5 complex, RGMB physically bridges NEO1 and GDF5, suggesting cross-talk between the GDF5 and NEO1 signaling pathways. Our crystal structures, combined with structure-guided mutagenesis of RGMs and BMP ligands, binding studies, and cellular assays suggest that RGMs inhibit GDF5 signaling by competing with GDF5 type 1 receptors. While our crystal structure analysis and in vitro binding data initially pointed towards a simple competition mechanism between RGMs and type 1 receptors as a possible basis for RGM-mediated GDF5 inhibition, further experiments utilizing BMP2-mimicking GDF5 variants clearly indicate a more complex mechanism that explains how RGMs can act as a functionality-changing switch for two structurally and biochemically similar signaling molecules. Repulsive guidance molecules lock growth differentiation factor 5 in an inhibitory complex.,Malinauskas T, Peer TV, Bishop B, Mueller TD, Siebold C Proc Natl Acad Sci U S A. 2020 Jun 23. pii: 2000561117. doi:, 10.1073/pnas.2000561117. PMID:32576689[16] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. 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