Assembly Mechanism of Mucin and von Willebrand Factor Polymers

Gabriel Javitt; Lev Khmelnitsky; Lis Albert; Lavi Shlomo Bigman; Nadav Elad; David Morgenstern; Tal Ilani; Yaakov Levy; Ron Diskin; Deborah Fass

doi:10.1016/j.cell.2020.09.021

Assembly Mechanism of Mucin and von Willebrand Factor Polymers

Gabriel Javitt, Lev Khmelnitsky, Lis Albert, Lavi Shlomo Bigman, Nadav Elad, David Morgenstern, Tal Ilani, Yaakov Levy, Ron Diskin, Deborah Fass^*

^*Corresponding author for this work

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

85 Citations (Scopus)

Abstract

The respiratory and intestinal tracts are exposed to physical and biological hazards accompanying the intake of air and food. Likewise, the vasculature is threatened by inflammation and trauma. Mucin glycoproteins and the related von Willebrand factor guard the vulnerable cell layers in these diverse systems. Colon mucins additionally house and feed the gut microbiome. Here, we present an integrated structural analysis of the intestinal mucin MUC2. Our findings reveal the shared mechanism by which complex macromolecules responsible for blood clotting, mucociliary clearance, and the intestinal mucosal barrier form protective polymers and hydrogels. Specifically, cryo-electron microscopy and crystal structures show how disulfide-rich bridges and pH-tunable interfaces control successive assembly steps in the endoplasmic reticulum and Golgi apparatus. Remarkably, a densely O-glycosylated mucin domain performs an organizational role in MUC2. The mucin assembly mechanism and its adaptation for hemostasis provide the foundation for rational manipulation of barrier function and coagulation.

Original language	English
Pages (from-to)	717-729.e16
Number of pages	23
Journal	Cell
Volume	183
Issue number	3
Early online date	7 Oct 2020
DOIs	https://doi.org/10.1016/j.cell.2020.09.021
Publication status	Published - 29 Oct 2020

Funding

The authors acknowledge Karin Strijbis, Emmanuel Levy, and Harry Greenblatt for helpful suggestions. This work was supported by the European Research Council ( 310649 ), by the I-CORE Program of the Planning and Budgeting Committee and the Israel Science Foundation ( 1775/12 ), and by a research grant from the Center for Scientific Excellence at the Weizmann Institute of Science . Conceptualization, G.J. and D.F.; Methodology, R.D., N.E., Y.L., and D.M.; Investigation, G.J., L.K., D.F., L.A., N.E., T.I., L.S.B., and D.M.; Writing – Original Draft, G.J. and D.F.; Writing – Review & Editing, all authors; Funding Acquisition, D.F.; Supervision, D.F. and Y.L.

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2020.09.021Licence: CC BY-NC-ND

Cite this

@article{406354a9d9354cecb2d9494e4dd510b6,

title = "Assembly Mechanism of Mucin and von Willebrand Factor Polymers",

abstract = "The respiratory and intestinal tracts are exposed to physical and biological hazards accompanying the intake of air and food. Likewise, the vasculature is threatened by inflammation and trauma. Mucin glycoproteins and the related von Willebrand factor guard the vulnerable cell layers in these diverse systems. Colon mucins additionally house and feed the gut microbiome. Here, we present an integrated structural analysis of the intestinal mucin MUC2. Our findings reveal the shared mechanism by which complex macromolecules responsible for blood clotting, mucociliary clearance, and the intestinal mucosal barrier form protective polymers and hydrogels. Specifically, cryo-electron microscopy and crystal structures show how disulfide-rich bridges and pH-tunable interfaces control successive assembly steps in the endoplasmic reticulum and Golgi apparatus. Remarkably, a densely O-glycosylated mucin domain performs an organizational role in MUC2. The mucin assembly mechanism and its adaptation for hemostasis provide the foundation for rational manipulation of barrier function and coagulation.",

author = "Gabriel Javitt and Lev Khmelnitsky and Lis Albert and Bigman, {Lavi Shlomo} and Nadav Elad and David Morgenstern and Tal Ilani and Yaakov Levy and Ron Diskin and Deborah Fass",

year = "2020",

month = oct,

day = "29",

doi = "10.1016/j.cell.2020.09.021",

language = "English",

volume = "183",

pages = "717--729.e16",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "3",

}

TY - JOUR

T1 - Assembly Mechanism of Mucin and von Willebrand Factor Polymers

AU - Javitt, Gabriel

AU - Khmelnitsky, Lev

AU - Albert, Lis

AU - Bigman, Lavi Shlomo

AU - Elad, Nadav

AU - Morgenstern, David

AU - Ilani, Tal

AU - Levy, Yaakov

AU - Diskin, Ron

AU - Fass, Deborah

PY - 2020/10/29

Y1 - 2020/10/29

N2 - The respiratory and intestinal tracts are exposed to physical and biological hazards accompanying the intake of air and food. Likewise, the vasculature is threatened by inflammation and trauma. Mucin glycoproteins and the related von Willebrand factor guard the vulnerable cell layers in these diverse systems. Colon mucins additionally house and feed the gut microbiome. Here, we present an integrated structural analysis of the intestinal mucin MUC2. Our findings reveal the shared mechanism by which complex macromolecules responsible for blood clotting, mucociliary clearance, and the intestinal mucosal barrier form protective polymers and hydrogels. Specifically, cryo-electron microscopy and crystal structures show how disulfide-rich bridges and pH-tunable interfaces control successive assembly steps in the endoplasmic reticulum and Golgi apparatus. Remarkably, a densely O-glycosylated mucin domain performs an organizational role in MUC2. The mucin assembly mechanism and its adaptation for hemostasis provide the foundation for rational manipulation of barrier function and coagulation.

AB - The respiratory and intestinal tracts are exposed to physical and biological hazards accompanying the intake of air and food. Likewise, the vasculature is threatened by inflammation and trauma. Mucin glycoproteins and the related von Willebrand factor guard the vulnerable cell layers in these diverse systems. Colon mucins additionally house and feed the gut microbiome. Here, we present an integrated structural analysis of the intestinal mucin MUC2. Our findings reveal the shared mechanism by which complex macromolecules responsible for blood clotting, mucociliary clearance, and the intestinal mucosal barrier form protective polymers and hydrogels. Specifically, cryo-electron microscopy and crystal structures show how disulfide-rich bridges and pH-tunable interfaces control successive assembly steps in the endoplasmic reticulum and Golgi apparatus. Remarkably, a densely O-glycosylated mucin domain performs an organizational role in MUC2. The mucin assembly mechanism and its adaptation for hemostasis provide the foundation for rational manipulation of barrier function and coagulation.

U2 - 10.1016/j.cell.2020.09.021

DO - 10.1016/j.cell.2020.09.021

M3 - Article

C2 - 33031746

AN - SCOPUS:85094568158

SN - 0092-8674

VL - 183

SP - 717-729.e16

JO - Cell

JF - Cell

IS - 3

ER -

Assembly Mechanism of Mucin and von Willebrand Factor Polymers

Abstract

Funding

All Science Journal Classification (ASJC) codes

Access to Document

Fingerprint

Cite this