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The structures of the neurotrophin 4 homodimer and the brain-derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site

Published online by Cambridge University Press:  01 December 1999

ROBERT C. ROBINSON ,
CZESLAW RADZIEJEWSKI ,
GLEN SPRAGGON ,
JASON GREENWALD ,
MIKEY R. KOSTURA ,
LESLIE D. BURTNICK ,
DAVID I. STUART ,
SENYON CHOE  and
E. YVONNE JONES
ROBERT C. ROBINSON
Affiliation:
Structural Biology Laboratory, The Salk Institute, La Jolla, California 92037
CZESLAW RADZIEJEWSKI
Affiliation:
Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591
GLEN SPRAGGON
Affiliation:
Center for Molecular Genetics, University of California, San Diego, La Jolla, California 92093-0634
JASON GREENWALD
Affiliation:
Structural Biology Laboratory, The Salk Institute, La Jolla, California 92037 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0634
MIKEY R. KOSTURA
Affiliation:
Structural Biology Laboratory, The Salk Institute, La Jolla, California 92037 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0634
LESLIE D. BURTNICK
Affiliation:
Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T1Z1, Canada
DAVID I. STUART
Affiliation:
Laboratory of Molecular Biophysics & Oxford Centre for Molecular Sciences, Department of Biochemistry, Rex Richards Building, South Parks Road, Oxford University, Oxford OX1 3QU, United Kingdom
SENYON CHOE
Affiliation:
Structural Biology Laboratory, The Salk Institute, La Jolla, California 92037
E. YVONNE JONES
Affiliation:
Laboratory of Molecular Biophysics & Oxford Centre for Molecular Sciences, Department of Biochemistry, Rex Richards Building, South Parks Road, Oxford University, Oxford OX1 3QU, United Kingdom
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Abstract

The neurotrophins are growth factors that are involved in the development and survival of neurons. Neurotrophin release by a target tissue results in neuron growth along the neurotrophin concentration gradient, culminating in the eventual innervation of the target tissue. These activities are mediated through trk cell surface receptors. We have determined the structures of the heterodimer formed between brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NT4), as well as the structure of homodimer of NT4. We also present the structure of the Neurotrophin 3 homodimer, which is refined to higher resolution than previously published. These structures provide the first views of the architecture of the NT4 protomer. Comparison of the surface of a model of the BDNF homodimer with the structures of the neurotrophin homodimers reveals common features that may be important in the binding between the neurotrophins and their receptors. In particular, there exists an analogous region on the surface of each neurotrophin that is likely to be involved in trk receptor binding. Variations in sequence on the periphery of this common region serve to confer trk receptor specificity.

Keywords

crystallographynerve growth factorreceptor
Type
Research Article
Information
Protein Science , Volume 8 , Issue 12 , December 1999 , pp. 2589 - 2597
Copyright
© 1999 The Protein Society

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