The structure of MESD45-184 brings light into the mechanism of LDLR family folding

Christian Köhler; Janet K. Lighthouse; Tobias Werther; Olav M. Andersen; Annette Diehl; Peter Schmieder; Jianguang Du; Bernadette C. Holdener; Hartmut Oschkinat

doi:10.1016/j.str.2010.12.022

The structure of MESD45-184 brings light into the mechanism of LDLR family folding

Christian Köhler
, Janet K. Lighthouse
, Tobias Werther
, Olav M. Andersen
, Annette Diehl
, Peter Schmieder
, Jianguang Du
, Bernadette C. Holdener
, Hartmut Oschkinat

Biochemistry and Cell Biology

Leibniz Institute for Molecular Pharmacology
Free University of Berlin
Stony Brook University
Aarhus University

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Mesoderm development (MESD) is a 224 amino acid mouse protein that acts as a molecular chaperone for the low-density lipoprotein receptor (LDLR) family. Here, we provide evidence that the region 45-184 of MESD is essential and sufficient for this function and suggest a model for its mode of action. NMR studies reveal a β-α-β-β-α-β core domain with an α-helical N-terminal extension that interacts with the β sheet in a dynamic manner. As a result, the structural ensemble contains open (active) and closed (inactive) forms, allowing for regulation of chaperone activity through substrate binding. The mutant W61R, which is lethal in Drosophila, adopts only the open state. The receptor motif recognized by MESD was identified by in vitro-binding studies. Furthermore, in vivo functional evidence for the relevance of the identified contact sites in MESD is provided.

Original language	English
Pages (from-to)	337-348
Number of pages	12
Journal	Structure
Volume	19
Issue number	3
DOIs	https://doi.org/10.1016/j.str.2010.12.022
State	Published - Mar 9 2011

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10.1016/j.str.2010.12.022

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title = "The structure of MESD45-184 brings light into the mechanism of LDLR family folding",

abstract = "Mesoderm development (MESD) is a 224 amino acid mouse protein that acts as a molecular chaperone for the low-density lipoprotein receptor (LDLR) family. Here, we provide evidence that the region 45-184 of MESD is essential and sufficient for this function and suggest a model for its mode of action. NMR studies reveal a β-α-β-β-α-β core domain with an α-helical N-terminal extension that interacts with the β sheet in a dynamic manner. As a result, the structural ensemble contains open (active) and closed (inactive) forms, allowing for regulation of chaperone activity through substrate binding. The mutant W61R, which is lethal in Drosophila, adopts only the open state. The receptor motif recognized by MESD was identified by in vitro-binding studies. Furthermore, in vivo functional evidence for the relevance of the identified contact sites in MESD is provided.",

author = "Christian K{\"o}hler and Lighthouse, \{Janet K.\} and Tobias Werther and Andersen, \{Olav M.\} and Annette Diehl and Peter Schmieder and Jianguang Du and Holdener, \{Bernadette C.\} and Hartmut Oschkinat",

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TY - JOUR

T1 - The structure of MESD45-184 brings light into the mechanism of LDLR family folding

AU - Köhler, Christian

AU - Lighthouse, Janet K.

AU - Werther, Tobias

AU - Andersen, Olav M.

AU - Diehl, Annette

AU - Schmieder, Peter

AU - Du, Jianguang

AU - Holdener, Bernadette C.

AU - Oschkinat, Hartmut

PY - 2011/3/9

Y1 - 2011/3/9

N2 - Mesoderm development (MESD) is a 224 amino acid mouse protein that acts as a molecular chaperone for the low-density lipoprotein receptor (LDLR) family. Here, we provide evidence that the region 45-184 of MESD is essential and sufficient for this function and suggest a model for its mode of action. NMR studies reveal a β-α-β-β-α-β core domain with an α-helical N-terminal extension that interacts with the β sheet in a dynamic manner. As a result, the structural ensemble contains open (active) and closed (inactive) forms, allowing for regulation of chaperone activity through substrate binding. The mutant W61R, which is lethal in Drosophila, adopts only the open state. The receptor motif recognized by MESD was identified by in vitro-binding studies. Furthermore, in vivo functional evidence for the relevance of the identified contact sites in MESD is provided.

AB - Mesoderm development (MESD) is a 224 amino acid mouse protein that acts as a molecular chaperone for the low-density lipoprotein receptor (LDLR) family. Here, we provide evidence that the region 45-184 of MESD is essential and sufficient for this function and suggest a model for its mode of action. NMR studies reveal a β-α-β-β-α-β core domain with an α-helical N-terminal extension that interacts with the β sheet in a dynamic manner. As a result, the structural ensemble contains open (active) and closed (inactive) forms, allowing for regulation of chaperone activity through substrate binding. The mutant W61R, which is lethal in Drosophila, adopts only the open state. The receptor motif recognized by MESD was identified by in vitro-binding studies. Furthermore, in vivo functional evidence for the relevance of the identified contact sites in MESD is provided.

UR - https://www.scopus.com/pages/publications/79952466448

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DO - 10.1016/j.str.2010.12.022

M3 - Article

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AN - SCOPUS:79952466448

SN - 0969-2126

VL - 19

SP - 337

EP - 348

JO - Structure

JF - Structure

IS - 3

ER -

The structure of MESD45-184 brings light into the mechanism of LDLR family folding

Abstract

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