Larry R. Jones

School of Medicine, Medicine, Cardiology

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Role of leucine 31 of phospholamban in structural and functional interactions with the ca²⁺ pump of cardiac sarcoplasmic reticulum

Zhenhui Chen; David L. Stokes; Larry R. Jones (Profiled Authors: Zhenhui Chen; Larry R. Jones)

Journal of Biological Chemistry. 2005;280(11):10530-10539.

The ability of two loss-of-function mutants, L31A and L31C, of phospholamban (PLB) to bind to and inhibit the Ca²⁺ pump of cardiac sarcoplasmic reticulum (SERCA2a) was investigated using a molecular cross-linking approach. Leu³¹ of PLB, located at the cytoplasmic membrane boundary, is a critical amino acid shown previously to be essential for Ca²⁺-ATPase inhibition. We observed that L31A or L31C mutations of PLB prevented the inhibition of Ca²⁺-ATPase activity and disabled the cross-linking of N27C and N30C of PLB to Lys³²⁸ and Cys ³¹⁸ of SERCA2a. Although L31C-PLB failed to cross-link to any Cys or Lys residue of wild-type SERCA2a, L31C did cross-link with high efficiency to T317C of SERCA2a with use of the homobifunctional sulfhydryl cross-linking reagent, 1,6-bismaleimidohexane. This places Leu³¹ of PLB within 10 Å of Thr³¹⁷ of SERCA2a in the M4 helix. Thus, contrary to previous suggestions, PLB with loss-of-function mutations at Leu³¹ retains the ability to bind to SERCA2a, despite losing inhibitory activity. Cross-linking of L31C-PLB to T317C-SERCA2a occurred only in the absence of Ca²⁺ and in the presence of nucleotide and was prevented by thapsigargin and by anti-PLB antibody, demonstrating for a fourth cross-linking pair that PLB interacts near M4 only when the Ca²⁺ pump is in the Ca²⁺-free, nucleotide-bound E2 conformation, but not in the E2 state inhibited by thapsigargin. L31I-PLB retained full functional and cross-linking activity, suggesting that a bulky hydrophobic residue at position 31 of PLB is essential for productive interaction with SERCA2a. A model for the three-dimensional structure of the interaction site is proposed. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

PMID: 15644311    

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