Solution structure of human myeloid-derived growth factor suggests a conserved function in the endoplasmic reticulum

Valeriu Bortnov; Marco Tonelli; Woonghee Lee; Ziqing Lin; Douglas S. Annis; Omar N. Demerdash; Alex Bateman; Julie C. Mitchell; Ying Ge; John L. Markley; Deane F. Mosher

doi:10.1038/s41467-019-13577-5

Solution structure of human myeloid-derived growth factor suggests a conserved function in the endoplasmic reticulum

Valeriu Bortnov, Marco Tonelli, Woonghee Lee, Ziqing Lin, Douglas S. Annis, Omar N. Demerdash, Alex Bateman, Julie C. Mitchell, Ying Ge, John L. Markley, Deane F. Mosher

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14 Scopus citations

Abstract

Human myeloid-derived growth factor (hMYDGF) is a 142-residue protein with a C-terminal endoplasmic reticulum (ER) retention sequence (ERS). Extracellular MYDGF mediates cardiac repair in mice after anoxic injury. Although homologs of hMYDGF are found in eukaryotes as distant as protozoans, its structure and function are unknown. Here we present the NMR solution structure of hMYDGF, which consists of a short α-helix and ten β-strands distributed in three β-sheets. Conserved residues map to the unstructured ERS, loops on the face opposite the ERS, and the surface of a cavity underneath the conserved loops. The only protein or portion of a protein known to have a similar fold is the base domain of VNN1. We suggest, in analogy to the tethering of the VNN1 nitrilase domain to the plasma membrane via its base domain, that MYDGF complexed to the KDEL receptor binds cargo via its conserved residues for transport to the ER.

Original language	English
Article number	5612
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13577-5
State	Published - Dec 1 2019

Funding

We thank and acknowledge the support of William Milo Westler at NMRFAM for his input on the hMYDGF NMR structure; Ronnie Frederick for offering his protocols, expertise, and reagents for producing isotopically labeled protein; and Darrell McCaslin for offering advice on conducting CD experiments and interpreting results. V.B., D.S.A., and D.F.M. were supported by NIH grants P01 HL088594 and R01 AI125390. M.T., W.L., and J.L.M. were supported by NIH grant P41 GM103399. This study made use of the National Magnetic Resonance Facility at Madison, which is supported by NIH grant P41 GM103399, formerly P41 RR002301. Equipment was purchased with funds from the University of Wisconsin-Madison, the NIH (P41 GM103399, S10 RR002781, S10 RR008438, S10 RR023438, S10 RR025062, S10 RR029220), and the NSF (DMB-8415048, OIA-9977486, BIR-9214394). Z.L. and Y.G. acknowledge top-down proteomics software grant R01 GM125085 and high-end instrument grant S10 OD018475.

Funders	Funder number
National Science Foundation	OIA-9977486
National Institutes of Health
National Heart, Lung, and Blood Institute	P01 HL088594
NIH Office of the Director	S10 OD018475
National Institute of General Medical Sciences	R01 GM125085, P41GM103399
National Institute of Allergy and Infectious Diseases	R01 AI125390
National Center for Research Resources	P41 RR002301
Division of Biological Infrastructure	DMB-8415048, BIR-9214394
National Sleep Foundation
University of Wisconsin-Madison	S10 RR029220, S10 RR023438, S10 RR025062, S10 RR008438, S10 RR002781

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10.1038/s41467-019-13577-5

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title = "Solution structure of human myeloid-derived growth factor suggests a conserved function in the endoplasmic reticulum",

abstract = "Human myeloid-derived growth factor (hMYDGF) is a 142-residue protein with a C-terminal endoplasmic reticulum (ER) retention sequence (ERS). Extracellular MYDGF mediates cardiac repair in mice after anoxic injury. Although homologs of hMYDGF are found in eukaryotes as distant as protozoans, its structure and function are unknown. Here we present the NMR solution structure of hMYDGF, which consists of a short α-helix and ten β-strands distributed in three β-sheets. Conserved residues map to the unstructured ERS, loops on the face opposite the ERS, and the surface of a cavity underneath the conserved loops. The only protein or portion of a protein known to have a similar fold is the base domain of VNN1. We suggest, in analogy to the tethering of the VNN1 nitrilase domain to the plasma membrane via its base domain, that MYDGF complexed to the KDEL receptor binds cargo via its conserved residues for transport to the ER.",

author = "Valeriu Bortnov and Marco Tonelli and Woonghee Lee and Ziqing Lin and Annis, {Douglas S.} and Demerdash, {Omar N.} and Alex Bateman and Mitchell, {Julie C.} and Ying Ge and Markley, {John L.} and Mosher, {Deane F.}",

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AU - Tonelli, Marco

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AU - Lin, Ziqing

AU - Annis, Douglas S.

AU - Demerdash, Omar N.

AU - Bateman, Alex

AU - Mitchell, Julie C.

AU - Ge, Ying

AU - Markley, John L.

AU - Mosher, Deane F.

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N2 - Human myeloid-derived growth factor (hMYDGF) is a 142-residue protein with a C-terminal endoplasmic reticulum (ER) retention sequence (ERS). Extracellular MYDGF mediates cardiac repair in mice after anoxic injury. Although homologs of hMYDGF are found in eukaryotes as distant as protozoans, its structure and function are unknown. Here we present the NMR solution structure of hMYDGF, which consists of a short α-helix and ten β-strands distributed in three β-sheets. Conserved residues map to the unstructured ERS, loops on the face opposite the ERS, and the surface of a cavity underneath the conserved loops. The only protein or portion of a protein known to have a similar fold is the base domain of VNN1. We suggest, in analogy to the tethering of the VNN1 nitrilase domain to the plasma membrane via its base domain, that MYDGF complexed to the KDEL receptor binds cargo via its conserved residues for transport to the ER.

AB - Human myeloid-derived growth factor (hMYDGF) is a 142-residue protein with a C-terminal endoplasmic reticulum (ER) retention sequence (ERS). Extracellular MYDGF mediates cardiac repair in mice after anoxic injury. Although homologs of hMYDGF are found in eukaryotes as distant as protozoans, its structure and function are unknown. Here we present the NMR solution structure of hMYDGF, which consists of a short α-helix and ten β-strands distributed in three β-sheets. Conserved residues map to the unstructured ERS, loops on the face opposite the ERS, and the surface of a cavity underneath the conserved loops. The only protein or portion of a protein known to have a similar fold is the base domain of VNN1. We suggest, in analogy to the tethering of the VNN1 nitrilase domain to the plasma membrane via its base domain, that MYDGF complexed to the KDEL receptor binds cargo via its conserved residues for transport to the ER.

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Solution structure of human myeloid-derived growth factor suggests a conserved function in the endoplasmic reticulum

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