Disease-linked mutations cause exposure of a protein quality control degron

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Standard

Disease-linked mutations cause exposure of a protein quality control degron. / Kampmeyer, Caroline; Larsen-Ledet, Sven; Wagnkilde, Morten Rose; Michelsen, Mathias; Iversen, Henriette K. M.; Nielsen, Sofie V.; Lindemose, Søren; Caregnato, Alberto; Ravid, Tommer; Stein, Amelie; Teilum, Kaare; Lindorff-Larsen, Kresten; Hartmann-Petersen, Rasmus.

I: Structure, Bind 30, Nr. 9, 2022, s. 1245-1253.e5.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Kampmeyer, C, Larsen-Ledet, S, Wagnkilde, MR, Michelsen, M, Iversen, HKM, Nielsen, SV, Lindemose, S, Caregnato, A, Ravid, T, Stein, A, Teilum, K, Lindorff-Larsen, K & Hartmann-Petersen, R 2022, 'Disease-linked mutations cause exposure of a protein quality control degron', Structure, bind 30, nr. 9, s. 1245-1253.e5. https://doi.org/10.1016/j.str.2022.05.016

APA

Kampmeyer, C., Larsen-Ledet, S., Wagnkilde, M. R., Michelsen, M., Iversen, H. K. M., Nielsen, S. V., Lindemose, S., Caregnato, A., Ravid, T., Stein, A., Teilum, K., Lindorff-Larsen, K., & Hartmann-Petersen, R. (2022). Disease-linked mutations cause exposure of a protein quality control degron. Structure, 30(9), 1245-1253.e5. https://doi.org/10.1016/j.str.2022.05.016

Vancouver

Kampmeyer C, Larsen-Ledet S, Wagnkilde MR, Michelsen M, Iversen HKM, Nielsen SV o.a. Disease-linked mutations cause exposure of a protein quality control degron. Structure. 2022;30(9):1245-1253.e5. https://doi.org/10.1016/j.str.2022.05.016

Author

Kampmeyer, Caroline ; Larsen-Ledet, Sven ; Wagnkilde, Morten Rose ; Michelsen, Mathias ; Iversen, Henriette K. M. ; Nielsen, Sofie V. ; Lindemose, Søren ; Caregnato, Alberto ; Ravid, Tommer ; Stein, Amelie ; Teilum, Kaare ; Lindorff-Larsen, Kresten ; Hartmann-Petersen, Rasmus. / Disease-linked mutations cause exposure of a protein quality control degron. I: Structure. 2022 ; Bind 30, Nr. 9. s. 1245-1253.e5.

Bibtex

@article{021f3030ada042d1be1b2fc9735def21,

title = "Disease-linked mutations cause exposure of a protein quality control degron",

abstract = "More than half of disease-causing missense variants are thought to lead to protein degradation, but the molecular mechanism of how these variants are recognized by the cell remains enigmatic. Degrons are stretches of amino acids that help mediate recognition by E3 ligases and thus confer protein degradation via the ubiquitin-proteasome system. While degrons that mediate controlled degradation of, for example, signaling components and cell-cycle regulators are well described, so-called protein-quality-control degrons that mediate the degradation of destabilized proteins are poorly understood. Here, we show that disease-linked dihydrofolate reductase (DHFR) missense variants are structurally destabilized and chaperone-dependent proteasome targets. We find two regions in DHFR that act as degrons, and the proteasomal turnover of one of these was dependent on the molecular chaperone Hsp70. Structural analyses by nuclear magnetic resonance (NMR) and hydrogen/deuterium exchange revealed that this degron is buried in wild-type DHFR but becomes transiently exposed in the disease-linked missense variants.",

keywords = "chaperone, conformational diseases, proteasome, protein degradation, protein misfolding, protein quality control, protein stability, protein unfolding, proteostasis, ubiquitin",

author = "Caroline Kampmeyer and Sven Larsen-Ledet and Wagnkilde, {Morten Rose} and Mathias Michelsen and Iversen, {Henriette K. M.} and Nielsen, {Sofie V.} and S{\o}ren Lindemose and Alberto Caregnato and Tommer Ravid and Amelie Stein and Kaare Teilum and Kresten Lindorff-Larsen and Rasmus Hartmann-Petersen",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",

year = "2022",

doi = "10.1016/j.str.2022.05.016",

language = "English",

volume = "30",

pages = "1245--1253.e5",

journal = "Structure",

issn = "0969-2126",

publisher = "Cell Press",

number = "9",

}

RIS

TY - JOUR

T1 - Disease-linked mutations cause exposure of a protein quality control degron

AU - Kampmeyer, Caroline

AU - Larsen-Ledet, Sven

AU - Wagnkilde, Morten Rose

AU - Michelsen, Mathias

AU - Iversen, Henriette K. M.

AU - Nielsen, Sofie V.

AU - Lindemose, Søren

AU - Caregnato, Alberto

AU - Ravid, Tommer

AU - Stein, Amelie

AU - Teilum, Kaare

AU - Lindorff-Larsen, Kresten

AU - Hartmann-Petersen, Rasmus

PY - 2022

Y1 - 2022

N2 - More than half of disease-causing missense variants are thought to lead to protein degradation, but the molecular mechanism of how these variants are recognized by the cell remains enigmatic. Degrons are stretches of amino acids that help mediate recognition by E3 ligases and thus confer protein degradation via the ubiquitin-proteasome system. While degrons that mediate controlled degradation of, for example, signaling components and cell-cycle regulators are well described, so-called protein-quality-control degrons that mediate the degradation of destabilized proteins are poorly understood. Here, we show that disease-linked dihydrofolate reductase (DHFR) missense variants are structurally destabilized and chaperone-dependent proteasome targets. We find two regions in DHFR that act as degrons, and the proteasomal turnover of one of these was dependent on the molecular chaperone Hsp70. Structural analyses by nuclear magnetic resonance (NMR) and hydrogen/deuterium exchange revealed that this degron is buried in wild-type DHFR but becomes transiently exposed in the disease-linked missense variants.

AB - More than half of disease-causing missense variants are thought to lead to protein degradation, but the molecular mechanism of how these variants are recognized by the cell remains enigmatic. Degrons are stretches of amino acids that help mediate recognition by E3 ligases and thus confer protein degradation via the ubiquitin-proteasome system. While degrons that mediate controlled degradation of, for example, signaling components and cell-cycle regulators are well described, so-called protein-quality-control degrons that mediate the degradation of destabilized proteins are poorly understood. Here, we show that disease-linked dihydrofolate reductase (DHFR) missense variants are structurally destabilized and chaperone-dependent proteasome targets. We find two regions in DHFR that act as degrons, and the proteasomal turnover of one of these was dependent on the molecular chaperone Hsp70. Structural analyses by nuclear magnetic resonance (NMR) and hydrogen/deuterium exchange revealed that this degron is buried in wild-type DHFR but becomes transiently exposed in the disease-linked missense variants.

KW - chaperone

KW - conformational diseases

KW - proteasome

KW - protein degradation

KW - protein misfolding

KW - protein quality control

KW - protein stability

KW - protein unfolding

KW - proteostasis

KW - ubiquitin

U2 - 10.1016/j.str.2022.05.016

DO - 10.1016/j.str.2022.05.016

M3 - Journal article

C2 - 35700725

AN - SCOPUS:85136560268

VL - 30

SP - 1245-1253.e5

JO - Structure

JF - Structure

SN - 0969-2126

IS - 9

ER -

ID: 322873845

Department of Biology