Title :
structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis
Abstract :
- Late infantile neuronal ceroid lipofuscinosis, a fatal neurodegenerative disease of childhood, is caused by mutations in the TPP1 gene that encodes tripeptidyl-peptidase I
- We show that purified TPP1 requires at least partial glycosylation for in vitro autoprocessing and proteolytic activity
- We crystallized the fully glycosylated TPP1 precursor under conditions that implied partial autocatalytic cleavage between the prosegment and the catalytic domain
- X-ray crystallographic analysis at 2.35 angstroms resolution reveals a globular structure with a subtilisin-like fold, a Ser475-Glu272-Asp360 catalytic triad, and an octahedrally coordinated Ca2 +-binding site that are characteristic features of the S53 sedolisin family of peptidases
- In contrast to other S53 peptidases , the TPP1 structure revealed steric constraints on the P4 substrate pocket explaining its preferential cleavage of tripeptides from the unsubstituted N terminus of proteins
- Two alternative conformations of the catalytic Asp276 are associated with the activation status of TPP1
- 28 disease-causing missense mutations are analyzed in the light of the TPP1 structure providing insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis
Output (sent_index, trigger,
protein,
sugar,
site):
- 3. glycosylated, , TPP1 precursor, -, -
Output(Part-Of) (sent_index,
protein,
site):
- 4. Ca2, site
- 5. -, tripeptides
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):