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Hereditary spastic paraplegias (HSPs) are a group of inherited neurological disorders characterized by distal, length-dependent axonal degeneration of the corticospinal motor neurons. There are over 40 distinct genetic loci for the HSPs (SPG1-48), and over 20 genes have been identified. There are both autosomal recessive, autosomal dominant, and X-linked modes of HSP. Previous studies have linked HSPs with MIT domain-containing proteins such as spartin (SPG20), spastin (SPG4) and the AAA ATPase Vps4, which generated interest in a protein MITD1 (microtubule interacting and transport- domain 1), of unknown function. Generally, MIT domains interact with proteins in the ESCRT-III (endosomal sorting complexes required for transport)-III complex that cycles between the state of a soluble monomer and higher-order assembly. In this study, we used yeast 2-hybrid assays to investigate the interaction domain of each protein. Using MITD1 as bait and all known ESCRT-III subunits as prey, we were able to discover that MITD1 binds robustly and selectively to several ESCRT-III proteins: CHMP1A/B (charged multivesicular body protein)-1A and -1B and Ist1 (increased sodium tolerance-1). We have narrowed down the MITD1 interaction domain within the ESCRT-III subunits through the use of deletion constructs. These data have helped us to close in on the interaction domain between MITD1 and the ESCRT-III subunits and facilitate crystallization of the protein complex.
Last Modified November 30, 2011