7mfd
Autoinhibited BRAF:(14-3-3)2:MEK complex with the BRAF RBD resolved
Structural highlights
DiseaseBRAF_HUMAN Note=Defects in BRAF are found in a wide range of cancers.[1] Defects in BRAF may be a cause of colorectal cancer (CRC) [MIM:114500.[2] Defects in BRAF are involved in lung cancer (LNCR) [MIM:211980. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.[3] [4] Defects in BRAF are involved in non-Hodgkin lymphoma (NHL) [MIM:605027. NHL is a cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss.[5] [6] Defects in BRAF are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant.[7] Defects in BRAF are the cause of Noonan syndrome type 7 (NS7) [MIM:613706. Noonan syndrome is a disorder characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits.[8] [9] Defects in BRAF are the cause of LEOPARD syndrome type 3 (LEOPARD3) [MIM:613707. LEOPARD3 is a disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.[10] [11] Note=A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation.[12] FunctionBRAF_HUMAN Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. Publication Abstract from PubMedRAF kinases are essential effectors of RAS, but how RAS binding initiates the conformational changes needed for autoinhibited RAF monomers to form active dimers has remained unclear. Here, we present cryo-electron microscopy structures of full-length BRAF complexes derived from mammalian cells: autoinhibited, monomeric BRAF:14-3-3(2):MEK and BRAF:14-3-3(2) complexes, and an inhibitor-bound, dimeric BRAF(2):14-3-3(2) complex, at 3.7, 4.1, and 3.9 A resolution, respectively. In both autoinhibited, monomeric structures, the RAS binding domain (RBD) of BRAF is resolved, revealing that the RBD forms an extensive contact interface with the 14-3-3 protomer bound to the BRAF C-terminal site and that key basic residues required for RBD-RAS binding are exposed. Moreover, through structure-guided mutational studies, our findings indicate that RAS-RAF binding is a dynamic process and that RBD residues at the center of the RBD:14-3-3 interface have a dual function, first contributing to RAF autoinhibition and then to the full spectrum of RAS-RBD interactions. Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding.,Martinez Fiesco JA, Durrant DE, Morrison DK, Zhang P Nat Commun. 2022 Jan 25;13(1):486. doi: 10.1038/s41467-022-28084-3. PMID:35078985[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
References
| ||||||||||||||||||||
