IQGAP1

1X0H, 2RR8, 3FAY, 3I6X882629875ENSG00000140575ENSMUSG00000030536P46940Q9JKF1NM_003870NM_016721NP_003861NP_057930Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed protein that in humans is encoded by the IQGAP1 gene. IQGAP1 is a scaffold protein involved in regulating various cellular processes ranging from organization of the actin cytoskeleton, transcription, and cellular adhesion to regulating the cell cycle.1x0h: Solution structure of the carboxyl-terminal RGC domain in human IQGAP1 Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed protein that in humans is encoded by the IQGAP1 gene. IQGAP1 is a scaffold protein involved in regulating various cellular processes ranging from organization of the actin cytoskeleton, transcription, and cellular adhesion to regulating the cell cycle. IQGAP1 was discovered in 1994.Its name stems from the fact that its RasGAP-related domain (GRD) has sequence homology to the Sar1 GTPase. It was hypothesized that IQGAP1 would act as a GTPase activating protein (GAP) protein, promoting the switch of ras GTPases from the active GTP to GDP-bound forms. However, despite the homology of IQGAP’s GAP domain to sar1 and the fact that IQGAP1 binds Rho GTPases Rac1 and Cdc42, IQGAP does not actually have GAP function. Instead, it binds the active (GTP-bound) forms of RAC1 and CDC42 with higher affinity than GDP-bound forms, and stabilizes the active form in vivo. IQGAP1 is now recognized as a protein scaffold that integrates signals regulating cell adhesion, actin cytoskeleton, the cell cycle, and other cellular functions. IQGAP is particularly interesting as a therapeutic target since it acts as a node for so many signaling pathways implicated in cancer progression. Analysis of IQGAP1 expression in human tissues has indicated that the scaffold is more or less ubiquitously expressed. It is usually found in the nucleus, plasma membrane, and cytoplasm. In other words it is found throughout the cell as well as throughout tissue types. Expression analysis has also indicated that IQGAP1 is overexpressed in many cancers, and in more aggressive colorectal and ovarian cancers, IQGAP1 is localized at the invasive front of the neoplasm, indicating a role in mobilization of the cells. Importantly, approximately 10% of genes that show increased expression in metastatic cells are IQGAP1 binding partners. IQGAP1 is a 190 kDa protein with 5 domains. A protein domain is a subsection of a protein that shows up multiple times in biology and can exist independently of the surrounding protein. It is very similar to subsections of other proteins, and could be cut out of the current protein, exist and function by itself, or be pasted in to a new protein strand and still function properly. Since this area of the protein is conserved in amino acid sequence and structure, it can be characterized by function or binding partner. IQGAP1 has 5 well-known domains separated by other amino acids. Starting at the N-terminus (or front of the protein), IQGAP1 contains a calponin homology domain (CHD), which mediates actin-binding and binds calponin. The WW, or poly-proline protein-protein domain, so named because of two functionally conserved tryptophans, W, is a protein-protein interaction domain that associates with proline-rich regions of other proteins. The WW domain is followed by 4 IQ motifs which form an IQ domain. This domain binds calmodulin, a protein known as a calcium sensor that can bind and regulate many target proteins. A GRD (rasGAP-related domain) follows the IQ domain. This domain is highly similar to the functional subunit of Ras GTPase-activating proteins (GAPs) and was thus thought to have GAP function. IQGAP1 does bind Rho GTPases CDC42 and RAC1, however, IQGAP1 is unusual in that it actually has no GAP function, and instead stabilizes the GTP-bound proteins in their active state.