9twb
Crystal structure of BRAF(val600):MEK1(pS222) complex with asymmetric dimer interface bound to ADP
Structural highlights
DiseaseMP2K1_HUMAN Defects in MAP2K1 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. FunctionMP2K1_HUMAN Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC), as well as in the fragmentation of the Golgi apparatus during mitosis.[1] [2] Publication Abstract from PubMedThe rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (RAF/MEK/ERK) signaling cascade regulates cell proliferation and differentiation and is frequently dysregulated in cancer. Approximately 90% of RAF-mutant cancers harbor mutations in B-type rapidly accelerated fibrosarcoma (BRAF). Its proto-oncogenicity is attributed to a four-residue N-terminal acidic (NtA) motif. Although a long-standing model proposes that the NtA promotes activating asymmetric RAF dimerization, the model lacks structural support. Here, we present structures of NtA-mediated asymmetric BRAF dimers bound to their substrate MEK1. Cellular and biochemical data show that the NtA is not required for KRAS-mediated BRAF recruitment to the plasma membrane but is required for the fully catalytically active state. The structure capturing BRAF in a post-catalytic state bound to Ser222-phosphorylated MEK1 further supports this model. The combination of structural and cellular data corroborates the model of NtA-driven asymmetry in BRAF activation and resolves a long-standing disconnect between RAF cancer genetics and structural biology. Mechanism of MEK1 phosphorylation by the N-terminal acidic motif-mediated asymmetric BRAF dimer.,Kondo Y, Notbohm J, Navas Camacho I, Nagy-Davidescu G, Mason T, Muhle J, Standfuss J, Perica T Mol Cell. 2026 Jul 21:S1097-2765(26)00452-1. doi: 10.1016/j.molcel.2026.06.039. PMID:42480522[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
