Regulation of C-type lectin antimicrobial activity by a flexible N-terminal prosegment

Sohini Mukherjee, Carrie L. Partch, Rebecca E. Lehotzky, Cecilia V. Whitham, Hiutung Chu, Charles L. Bevins, Kevin H. Gardner, Lora V. Hooper

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Members of the RegIII family of intestinal C-type lectins are directly antibacterial proteins that play a vital role in maintaining host-bacterial homeostasis in the mammalian gut, yet little is known about the mechanisms that regulate their biological activity. Here we show that the antibacterial activities of mouse RegIIIγ and its human ortholog, HIP/PAP, are tightly controlled by an inhibitory N-terminal prosegment that is removed by trypsin in vivo. NMR spectroscopy revealed a high degree of conformational flexibility in the HIP/PAP inhibitory prosegment, and mutation of either acidic prosegment residues or basic core protein residues disrupted prosegment inhibitory activity. NMR analyses of pro-HIP/PAP variants revealed distinctive colinear backbone amide chemical shift changes that correlated with antibacterial activity, suggesting that prosegment-HIP/PAP interactions are linked to a two-state conformational switch between biologically active and inactive protein states. These findings reveal a novel regulatory mechanism governing C-type lectin biological function and yield new insight into the control of intestinal innate immunity.

Original languageEnglish (US)
Pages (from-to)4881-4888
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number8
DOIs
StatePublished - Feb 20 2009

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C-Type Lectins
Hot isostatic pressing
Proteins
Innate Immunity
Amides
Trypsin
Chemical shift
Homeostasis
Magnetic Resonance Spectroscopy
Bioactivity
Nuclear magnetic resonance spectroscopy
Mutation
Switches
Nuclear magnetic resonance

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Mukherjee, S., Partch, C. L., Lehotzky, R. E., Whitham, C. V., Chu, H., Bevins, C. L., ... Hooper, L. V. (2009). Regulation of C-type lectin antimicrobial activity by a flexible N-terminal prosegment. Journal of Biological Chemistry, 284(8), 4881-4888. https://doi.org/10.1074/jbc.M808077200

Regulation of C-type lectin antimicrobial activity by a flexible N-terminal prosegment. / Mukherjee, Sohini; Partch, Carrie L.; Lehotzky, Rebecca E.; Whitham, Cecilia V.; Chu, Hiutung; Bevins, Charles L.; Gardner, Kevin H.; Hooper, Lora V.

In: Journal of Biological Chemistry, Vol. 284, No. 8, 20.02.2009, p. 4881-4888.

Research output: Contribution to journalArticle

Mukherjee S, Partch CL, Lehotzky RE, Whitham CV, Chu H, Bevins CL et al. Regulation of C-type lectin antimicrobial activity by a flexible N-terminal prosegment. Journal of Biological Chemistry. 2009 Feb 20;284(8):4881-4888. https://doi.org/10.1074/jbc.M808077200
Mukherjee, Sohini ; Partch, Carrie L. ; Lehotzky, Rebecca E. ; Whitham, Cecilia V. ; Chu, Hiutung ; Bevins, Charles L. ; Gardner, Kevin H. ; Hooper, Lora V. / Regulation of C-type lectin antimicrobial activity by a flexible N-terminal prosegment. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 8. pp. 4881-4888.
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