4ldq

Publication Abstract from PubMed

Metastatic melanoma is among the most intractable cancers to treat, where patients show resistance to therapy and limited survival time. A critical step in the development of metastatic melanoma is the acquisition of invasion and transition from thin to thick tumors on the skin, followed by invasion to lymph nodes. Prior studies have shown that metastatic melanoma is associated with dysregulation of RhoA and enhanced expression of a protein named "mediator of RhoA-dependent invasion (MRDI)". Importantly, MRDI is a "moonlighting" enzyme, with two distinct functions in melanoma cells. First, MRDI acts as a methylthioribose-1-phosphate (MTR-1-P) isomerase, catalyzing a critical step in methionine salvage. Second, MRDI promotes and is necessary for melanoma cell invasion, independent of its catalytic activity. Here, we demonstrate that MtnA, a bacterial MTR-1-P isomerase, rescues the methionine salvage function of MRDI, but is unable to rescue its role in invasion. We then solve the crystal structure of MRDI to a resolution of 2.5 A, in order to identify structural elements important for its invasion activity. We present this structure and its comparison with other MTR-1-P isomerases, and identify mutations within a region separate from the MTR-1-P binding site which interfere with invasion. Thus, structural elements in MRDI distal from the MTR-1-P catalytic site are responsible for the invasion phenotype.

Structure of MRDI Explains its Dual Function as a Metabolic Enzyme and a Mediator of Cell Invasion.,Templeton PD, Litman ES, Metzner SI, Ahn NG, Sousa MC Biochemistry. 2013 Jul 16. PMID:23859498^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.