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Structural Biophysics Laboratory (SBL)
Protein-Nucleic Acid Interaction Section

Research Projects: Structural biology study of the receptor associated protein, RAP

A histidine switch mediates the release of LRP receptors in the Golgi


The receptor associated protein (RAP) is an antagonist and molecular chaperone that binds tightly to low-density lipoprotein receptor related proteins (LRP) family members in the endoplasmic reticulum (ER). After escorting the receptor to the Golgi, RAP dissociates from receptors. The molecular mechanism of the dissociation has been unknown until now. The novel solution structure of RAP presented here reveals a striking increase in positively charged residues on the surface of RAP domains 2 and 3 due to protonation of solvent-exposed histidine side chains as the pH is reduced from a near neutral pH of the ER to the acidic pH of the Golgi. Structure-based mutagenesis studies in vitro and in cells confirm that the protonation of histidine in response to pH changes the binding/release. This histidine switch may serve as one of general mechanisms for regulating cell trafficking events. The results of the project have been published in several articles.

Lee D, Walsh JD, Mikhailenko I, Yu P, Migliorini M, Wu Y, Krueger S, Curtis JE, Harris B, Lockett S, Blacklow SC, Strickland DK, Wang YX.
RAP uses a histidine switch to regulate its interaction with LRP in the ER and Golgi. Mol Cell 22: 423-30, 2006.

Lee D, Walsh JD, Migliorini M, Yu P, Cai T, Schwieters CD, Krueger S, Strickland DK, Wang YX.
The structure of receptor-associated protein (RAP). Protein Sci. 16: 1628-40, 2007.

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