5hi2
From Proteopedia
BRAF Kinase domain b3aC loop deletion mutant in complex with sorafenib
Structural highlights
Disease[BRAF_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] Function[BRAF_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 PubMedActivating mutations in protein kinases drive many cancers. While how recurring point mutations affect kinase activity has been described, the effect of in-frame deletions is not well understood. We show that oncogenic deletions within the beta3-alphaC loop of HER2 and BRAF are analogous to the recurrent EGFR exon 19 deletions. We identify pancreatic carcinomas with BRAF deletions mutually exclusive with KRAS mutations. Crystal structures of BRAF deletions reveal the truncated loop restrains alphaC in an active "in" conformation, imparting resistance to inhibitors like vemurafenib that bind the alphaC "out" conformation. Characterization of loop length explains the prevalence of five amino acid deletions in BRAF, EGFR, and HER2 and highlights the importance of this region for kinase activity and inhibitor efficacy. Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2.,Foster SA, Whalen DM, Ozen A, Wongchenko MJ, Yin J, Yen I, Schaefer G, Mayfield JD, Chmielecki J, Stephens PJ, Albacker LA, Yan Y, Song K, Hatzivassiliou G, Eigenbrot C, Yu C, Shaw AS, Manning G, Skelton NJ, Hymowitz SG, Malek S Cancer Cell. 2016 Apr 11;29(4):477-93. doi: 10.1016/j.ccell.2016.02.010. Epub, 2016 Mar 17. PMID:26996308[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Non-specific serine/threonine protein kinase | Albacker, L | Chmielecki, J | Eigenbrot, C | Foster, S A | Hatzivassiliou, G | Hymowitz, S G | Malek, S | Manning, G | Mayfield, J | Ozen, A | Schaefer, G | Shaw, A S | Skelton, N J | Song, K | Stephens, P | Whalen, D M | Wongchenko, M | Yan, Y | Yin, J | Yu, C | Transferase-transferase inhibitor complex
