Human RAP Stable Mutant

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Human RAP Stable Mutant

This stable mutant form of human Receptor Associated Protein (RAP) is resistant to both pH and heat induced denaturation. The molecule binds to lipoprotein receptor-related protein 1 (LRP1) with high affinity and inhibits LRP1 function both in vitro and in vivo. The D3 domain of RAP, which unfolds at low pH causing dissociation from LRP1, has been stabilized with six mutations (1). Y260 and T297 are changed to cysteines to generate a novel disulfide bond between helices 2 and 3 while H257, H259, H268, and H290 are changed to phenylalanines. Human RAP Stable Mutant does not unfold at pH 5.5 and has a melting temperature of 73°C, more than 30 degrees above that of wild type RAP. It is also more resistant to trypsin and chymotrypsin mediated proteolysis. Human RAP Stable Mutant may be useful in multiple pathological settings where LRP1 blockade has shown to be effective. Produced recombinantly in E. coli. Endotoxin reduced by reverse-phase chromatography for cell based experiments and animal studies.

References
1. Joni M. Prasad, Mary Migliorini, Rebeca Galisteo, and Dudley K. Strickland. Generation of a Potent Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Antagonist by Engineering a Stable Form of the Receptor-associated Protein (RAP) D3 Domain. J. Biol. Chem. 2015 290: 17262-17268.

Gene ID: 4043
Swiss-Prot/UniProt ID: P30533

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4. Sashindranath M, Sales E, Daglas M et-al. The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans. Brain. 2012;135 (Pt): 3251-64. doi:10.1093/brain/aws178Free text at pubmedPubmed citation

5. Byun K, Gil SY, Namkoong C et-al. Clusterin/ApoJ enhances central leptin signaling through Lrp2-mediated endocytosis. EMBO Rep. 2014;doi:10.15252/embr.201338317Pubmed citation

6. Sen, A., T. J. Nelson, and D. L. Alkon. ‘Apoe4 And A  Oligomers Reduce BDNF Expression Via HDAC Nuclear Translocation’. Journal of Neuroscience 35.19 (2015): 7538-7551. Web. 5 June 2015. Link to article