Structure of mouse 7S NGF: a complex of nerve growth factor with four binding proteins

Bax, Benjamin ORCID: https://orcid.org/0000-0003-1940-3785, Blundell, Tom L, Murray-Rust, Judith and McDonald, Neil Q 1997. Structure of mouse 7S NGF: a complex of nerve growth factor with four binding proteins. Structure 5 (10) , pp. 1275-1285. 10.1016/S0969-2126(97)00280-3

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Abstract

Background: Nerve growth factor (NGF) is a neurotrophic factor that promotes the differentiation and survival of certain populations of neurons in the central and peripheral nervous systems. 7S NGF is an α2β2γ2 complex in which the β-NGF dimer (the active neurotrophin) is associated with two α-NGF and two γ-NGF subunits, which belong to the glandular kallikrein family of serine proteinases. The γ-NGF subunit is an active serine proteinase capable of processing the precursor form of β-NGF, whereas α-NGF is an inactive serine proteinase. The structure of 7S NGF could be used as a starting point to design inhibitors that prevent NGF binding to its receptors, as a potential treatment of neurodegenerative diseases. Results: The crystal structure of 7S NGF shows that the two γ-NGF subunits make extensive interactions with each other around the twofold axis of the complex and have the C-terminal residues of the β-NGF subunits bound within their active sites. The ‘activation domain’ of each of the α-NGF subunits is in an inactive (zymogen-like) conformation and makes extensive interactions with the β-NGF dimer. The two zinc ions that stabilize the complex are located at the relatively small interfaces between the α-NGF and γ-NGF subunits. Conclusions: The structure of 7S NGF shows how the twofold axis of the central β-NGF dimer organizes the symmetry of this multisubunit growth factor complex. The extensive surface of β-NGF buried within the 7S complex explains the lack of neurotrophic activity observed for 7S NGF. The regions of the β-NGF dimer that contact the α-NGF subunits overlap with those known to engage NGF receptors. Two disulphide-linked loops on α-NGF make multiple interactions with β-NGF and suggest that it might be possible to design peptides that inhibit the binding of β-NGF to its receptors.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Elsevier (Cell Press)
ISSN:	0969-2126
Date of Acceptance:	19 August 1997
Last Modified:	23 Oct 2022 14:03
URI:	https://orca.cardiff.ac.uk/id/eprint/112641

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