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Hydrocarbon-stapling stabilization of the reduced homodimerization interaction of hepatic cancer DAP12 transmembrane domain in water phase

Wenqing Tang, Chen Wang, Yingting Zhou, Jing Luo, Tao Ye, and Biwei Yang

Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Disease, Zhongshan Hospital, Fudan University, Shanghai, China

 

E-mail: taoye@yeah.net

Received: 9 August 2019  Accepted: 29 November 2019

Abstract:

DAP12 is an immunoreceptor tyrosine-based activation motif (ITAM)-bearing adapter protein that mediates signaling for multiple cell-surface receptors, and plays a key role in the immunoregulation and pathogenesis of hepatic cancer and liver disorders. The protein contains a 33 amino-acid, single-pass, α-helical transmembrane (TM) domain that can form homodimer in cell lipid membrane. Here, a systematic investigation of DAP12 TM homodimerization is performed at molecular level. An all-residue pairwise interaction potential profile is created, from which it is revealed that the packing tightness and effectiveness are not distributed evenly along the panhandling homodimerization interface. A core-interaction region that should confer high affinity and specificity to the homodimerization is identified, which corresponds to a reduced (14-mer) peptide segment 46IVVGDLVLTVLIAL59. It is revealed that both the full-length and reduced peptides can well fold into helical conformation in lipid environment, but exhibit large flexibility and intrinsic disorder in water phase. Here, the helical conformation of reduced peptide is stabilized by adding two all-hydrocarbon bridges across non-interfacial residue pairs (47,51) and (54,58). Circular dichroism indicates that the peptide helicity increases significantly upon the stapling; computational analysis and anisotropy assay confirm that the dimerization potency of stapled peptide is improved considerably relative to its unstapled counterpart in water phase.

Keywords: Molecular design; DNAX activation protein of 12 kDa; Peptide; Homodimerization; Hydrocarbon stapling; Hepatic cancer

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-019-01016-0

 

Chemical Papers 74 (7) 2153–2161 (2020)

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