Structure of the Survival Motor Neuron Protein (SMN)

Arizona State University-Tempe Campus, Tempe AZ

Investigators

Abstract

DESCRIPTION (provided by applicant): Spinal muscular atrophy, SMA, is a leading cause of death in infancy. This disease is a neurodegenerative disorder due to the loss of motor neurons that has 3 clinical forms. In all 3 cases, this autosomal-recessive disease arises from changes in a gene identified as SMN1, or survival motor neuron 1. How changes in this gene give rise to the observed clinical manifestations remains unknown. Some functions have been identified for this protein; however, these functions do not explain why cell death occurs in the motor neurons of SMA patients. A critical reason for our limited understanding is the lack of the three-dimensional (3D) structure of the encoded protein, SMN. Our overall goal is to develop a molecular understanding of the SMN protein. To achieve this, we plan to determine the three dimensional (3D) structure of the SMN protein using protein crystallography. In order to obtain enough protein for the crystallization trials, we are making use of expression systems that produce large amounts of pure protein. For 1 portion of the protein, the region encoded by axons 1-4, crystals and X-ray diffraction data have already been obtained yielding a preliminary model. We propose the completion of this model, the determination of the full-length SMN, and a truncated form found in SMA patients. Insight into the causes of the disease and the role of the SMN protein should be provided by the determination of the three-dimensional (3D) structure. At this point in time, there is no clinical treatment of motor neuron degeneration in SMA patients. To develop a molecular model of SMN, structural studies are proposed to determination of the structures of SMN with nucleic acids bound, with missense mutations, and with Gemin2 bound. These structural studies will be complemented by measurement of the respective binding constants. Together, these results should enhance our understanding of the molecular reasons for SMA and potentially lead to new strategies for the development of therapies.