The structure of tripeptidyl peptidase I (TPP1) provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis

Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive disease caused by mutations in the TPP1 gene resulting in functional defect of the gene product. Clinical symptoms usually begin after two years of age and comprise developmental stagnation, ataxia and epilepsy, finally leading to a complete loss of motor function, vision and speech by the age of ten. More than 50% of the LINCL associated genetic alterations are missense mutations that result in conformational distrubances. To elucidate the structural basis for these TPP1 mutants, we crystallized fully glycosylated TPP1. X-ray crystallographic analysis at 2.35Å resolution reveals a globular structure with a subtilisin-like fold, a S475-E272-D360 catalytic triad and an octahedrally coordinated Ca2+ binding site that are characteristic features of the S53 sedolisin family of serine proteases. On the basis of the resolved TPP1 structure we characterized the molecular effects of 28 missense mutations. These mutations either disrupt protein folding leading to instability or compromise the active center resulting in loss of proteolytic activity. Our results extend the understanding of the molecular mechanisms underlying LINCL and offer novel therapeutic options.