University of Oulu

Myllykoski, M. , Eichel, M. A., Jung, R. B., Kelm, S. , Werner, H. B. and Kursula, P. (2018), High‐affinity heterotetramer formation between the large myelin‐associated glycoprotein and the dynein light chain DYNLL1. J. Neurochem., 147: 764-783. doi:10.1111/jnc.14598

High-affinity heterotetramer formation between the large myelin-associated glycoprotein and the dynein light chain DYNLL1

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Author: Myllykoski, Matti1; Eichel, Maria A.2,3; Jung, Ramona B.2;
Organizations: 1Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
2Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany
3Georg August University School of Science, University of Göttingen, Göttingen, Germany
4Centre for Biomolecular Interactions Bremen (CBIB), University of Bremen, Bremen, Germany
5Department of Biomedicine, University of Bergen, Bergen, Norway
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe2019070822845
Language: English
Published: John Wiley & Sons, 2018
Publish Date: 2019-12-31
Description:

Abstract

The close association of myelinated axons and their myelin sheaths involves numerous intercellular molecular interactions. For example, myelin‐associated glycoprotein (MAG) mediates myelin‐to‐axon adhesion and signalling via molecules on the axonal surface. However, knowledge about intracellular binding partners of myelin proteins, including MAG, has remained limited. The two splice isoforms of MAG, S‐ and L‐MAG, display distinct cytoplasmic domains and spatiotemporal expression profiles. We used yeast two‐hybrid screening to identify interaction partners of L‐MAG and found the dynein light chain DYNLL1 (also termed dynein light chain 8). DYNLL1 homodimers are known to facilitate dimerization of target proteins. L‐MAG and DYNLL1 associate with high affinity, as confirmed with recombinant proteins in vitro. Structural analyses of the purified complex indicate that the DYNLL1‐binding segment is localized close to the L‐MAG C terminus, next to the Fyn kinase Tyr phosphorylation site. The crystal structure of the complex between DYNLL1 and its binding segment on L‐MAG shows 2 : 2 binding in a parallel arrangement, indicating a heterotetrameric complex. The homology between L‐MAG and previously characterized DYNLL1‐ligands is limited, and some details of binding site interactions are unique for L‐MAG. The structure of the complex between the entire L‐MAG cytoplasmic domain and DYNLL1, as well as that of the extracellular domain of MAG, were modelled based on small‐angle X‐ray scattering data, allowing structural insights into L‐MAG interactions on both membrane surfaces. Our data imply that DYNLL1 dimerizes L‐MAG, but not S‐MAG, through the formation of a specific 2 : 2 heterotetramer. This arrangement is likely to affect, in an isoform‐specific manner, the functions of MAG in adhesion and myelin‐to‐axon signalling.

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Series: Journal of neurochemistry
ISSN: 0022-3042
ISSN-E: 1471-4159
ISSN-L: 0022-3042
Volume: 147
Issue: 6
Pages: 764 - 783
DOI: 10.1111/jnc.14598
OADOI: https://oadoi.org/10.1111/jnc.14598
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
Copyright information: © 2018 International Society for Neurochemistry. This is the peer reviewed version of the following article: Myllykoski, M. , Eichel, M. A., Jung, R. B., Kelm, S. , Werner, H. B. and Kursula, P. (2018), High‐affinity heterotetramer formation between the large myelin‐associated glycoprotein and the dynein light chain DYNLL1. J. Neurochem., 147: 764-783. doi:10.1111/jnc.14598, which has been published in final form at https://doi.org/10.1111/jnc.14598. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.