Crystal Structure of Human Profilaggrin S100 Domain and Identification of Target Proteins Annexin II, Stratifin, and HSP27

The Journal of Investigative Dermatology
Christopher G BunickThomas A Steitz

Abstract

The fused-type S100 protein profilaggrin and its proteolytic products including filaggrin are important in the formation of a normal epidermal barrier; however, the specific function of the S100 calcium-binding domain in profilaggrin biology is poorly understood. To explore its molecular function, we determined a 2.2 Å-resolution crystal structure of the N-terminal fused-type S100 domain of human profilaggrin with bound calcium ions. The profilaggrin S100 domain formed a stable dimer, which contained two hydrophobic pockets that provide a molecular interface for protein interactions. Biochemical and molecular approaches demonstrated that three proteins, annexin II/p36, stratifin/14-3-3 sigma, and heat shock protein 27, bind to the N-terminal domain of human profilaggrin; one protein (stratifin) co-localized with profilaggrin in the differentiating granular cell layer of human skin. Together, these findings suggest a model where the profilaggrin N-terminus uses calcium-dependent and calcium-independent protein-protein interactions to regulate its involvement in keratinocyte terminal differentiation and incorporation into the cornified cell envelope.

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Citations

Mar 14, 2020·Science·Felipe Garcia QuirozElaine Fuchs
Sep 8, 2020·Journal of Dermatological Science·Alexander J HinbestChristopher G Bunick
Jan 20, 2021·Archives of Pharmacal Research·Yeonjoon Kim, Kyung-Min Lim
Feb 9, 2021·Frontiers in Cellular and Infection Microbiology·Dora E Corzo-LeónCarol A Munro

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Methods Mentioned

BETA
two-hybrid
co-immunoprecipitation
size-exclusion chromatography
light scattering
fluorescence spectroscopy
Y2H
immunoprecipitation

Software Mentioned

PyMOL Molecular Graphics System
Clustal Omega
MOLREP
PHENIX
Astra
INTERHLX
Adaptive Poisson - Boltzmann Software ( APBS )
UCSF Chimera
Coot Chimera
Hex Protein Docking

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