Pseudokinases kinase suppressor of Ras 1 and 2 (KSR1/2) are scaffolds that bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK). They dimerize with kinase-competent RAFs (ARAF, BRAF and CRAF) to stimulate catalysis allosterically []. This entry represents the N-terminal helical hairpin which, together with the SAM-like domain () constitutes the N-terminal regulatory region that mediates heterodimerization of BRAF with KSR1. Additionally, MEK binding to the kinase domain of KSR1 asymmetrically drives BRAF-KSR1 heterodimerization, resulting in the concomitant stimulation of BRAF catalytic activity towards free MEK molecules [].
Pseudokinases kinase suppressor of Ras 1 and 2 (KSR1/2) are scaffolds that bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK). They dimerize with kinase-competent RAFs (ARAF, BRAF and CRAF) to stimulate catalysis allosterically []. This entry represents the N-terminal helical hairpin which, together with the SAM-like domain () constitutes the N-terminal regulatory region that mediates heterodimerization of BRAF with KSR1. Additionally, MEK binding to the kinase domain of KSR1 asymmetrically drives BRAF-KSR1 heterodimerization, resulting in the concomitant stimulation of BRAF catalytic activity towards free MEK molecules [].
This SAM-like domain is found in kinase suppressor of Ras proteins, which are location-regulated scaffolding proteins connecting MEK to RAF []. This domain is part of the N-terminal regulatory region that mediates heterodimerization of BRAF with KSR1.
The function of the proteins in this entry is not currently known, but one of the human proteins () has been implicated in pilocytic astrocytomas [, , ]. In the majority of cases of pilocytic astrocytomas a tandem duplication produces an in-frame fusion of the gene encoding this protein and the BRAF oncogene. The resulting fusion protein has constitutive BRAF kinase activity and is capable of transforming cells.
RNF149, also known as DNA polymerase-transactivated protein 2, is an E3 ubiquitin-protein ligase that interacts with wild-type v-Raf murine sarcoma viral oncogene homologue B1 (BRAF), a RING domain-containing E3 ubiquitin ligase involved in control of gene transcription, translation, cytoskeletal organization, cell adhesion, and epithelial development. RNF149 induces the ubiquitination of wild-type BRAF and promotes its proteasome-dependent degradation. Mutated RNF149 has been found in some human breast, ovarian, and colorectal cancers. RNF149 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence [].
