+ Translate
+ Most Popular
The pigeon tick (Argas reflexus): its biology, ecology, and epidemiological aspects
Prevalence of hemoglobin abnormalities in Kebili (Tunisian South)
Lipogranuloma: a preventable complication of dacryocystorhinostomy
Value of basal plasma cortisol assays in the assessment of pituitary-adrenal insufficiency
Bees from the Belgian Congo. The acraensis group of Anthophora
Placing gingival retraction cord
Total serum IgE, allergy skin testing, and the radioallergosorbent test for the diagnosis of allergy in asthmatic children
Acariens plumicoles Analgesoidea parasites des oiseaux du Maroc
Injuries of terminal phalanges of the fingers in children
Biology of flowering and nectar production in pear (Pyrus communis)
Das Reliktvorkommen der Aspisviper (Vipera aspis L.) im Schwarzwald
Hydrological modelling of drained blanket peatland
Pathologic morphology and clinical significance of the anomalous origin of the left circumflex coronary artery from the right coronary artery. General review and autopsy analysis of 30 cases
Cyto genetic analyses of lymphocyte cultures after exposure to calcium cyclamate
Axelrodia riesei, a new characoid fish from Upper Rio Meta in Colombia With remarks concerning the genus Axelrodia and description of a similar, sympatric, Hyphessobrycon-species
Favorable evolution of a case of tuberculosis of pancreas under antibiotic action
RIFM fragrance ingredient safety assessment, Valencene, CAS Registry Number 4630-07-3
Parenteral microemulsions: an overview
Temperate pasture: management for grazing and conservation
Evaluation of a new coprocessed compound based on lactose and maize starch for tablet formulation
Thermal expansion and cracking of three confined water-saturated igneous rocks to 800C
Revision of the genera of the tribe Stigmoderini (Coleoptera: Buprestidae) a discussion of phylogenetic relationships
Anal tuberculosis. Report of a case
Gastric tuberculosis in the past and present
Adaptive responses of the cardiovascular system to prolonged spaceflight conditions: assessment with Holter monitoring

Three-dimensional structure of the human 'protective protein': Structure of the precursor form suggests a complex activation mechanism

Three-dimensional structure of the human 'protective protein': Structure of the precursor form suggests a complex activation mechanism

Structure 3(11): 1249-1259

ISSN/ISBN: 0969-2126

PMID: 8591035

DOI: 10.1016/s0969-2126(01)00260-x

Background: The human 'protective protein' (HPP) forms a multi-enzyme complex with beta-galactosidase and neuraminidase in the lysosomes, protecting these two glycosidases from degradation. In humans, deficiency of HPP leads to the lysosomal storage disease gdlactosialidosis. Proteolytic cleavage of the precursor form of HPP involves removal of a 2 kDa excision peptide and results in a carboxypeptidase activity. The physiological relevance of this activity is, as yet, unknown. Results: The crystal structure of the 108 kDa dimer of the precursor HPP has been elucidated by making extensive use of twofold density averaging. The monomer consists of a 'core' domain and a 'cap' domain. Comparison with the distantly related wheat serine carboxypeptidase dimer shows that the two subunits in the HPP dimer differ by 15 degree in mutual orientation. Also, the helical subdomain forming part of the cap domains is very different. In addition, the HPP precursor cap domain contains a 'maturation' subdomain of 49 residues which fills the active-site cleft. Merely removing the 'excision' peptide located in the maturation subdomain does not render the catalytic triad solvent accessible. Conclusions: The activation mechanism of HPP is unique among proteases with known structure. It differs from the serine proteases in that the active site is preformed in the zymogen, but is blocked by a maturation subdomain. In contrast to the zinc metalloproteases and aspartic proteases, the chain segment physically rendering the catalytic triad solvent inaccessible in HPP is not cleaved off to form the active enzyme. The activation must be a multi-step process involving removal of the excision peptide and major conformational changes of the maturation subdomain, whereas the conformation of the enzymatic machinery is probably almost, or completely, unaffected.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 009645967

Download citation: RISBibTeXText

Related references

Structure of the unliganded form of the proprotein convertase furin suggests activation by a substrate-induced mechanism. Proceedings of the National Academy of Sciences of the United States of America 113(40): 11196-11201, 2016

Precursor complex structure of pseudouridine synthase TruB suggests coupling of active site perturbations to an RNA-sequestering peripheral protein domain. Protein Science: a Publication of the Protein Society 14(8): 2201-2206, 2005

Structure determination of the human protective protein: twofold averaging reveals the three-dimensional structure of a domain which was entirely absent in the initial model. Acta Crystallographica. Section D Biological Crystallography 52(Pt 5): 923-936, 1996

Crystal structure of amyloid precursor-like protein 1 and heparin complex suggests a dual role of heparin in E2 dimerization. Proceedings of the National Academy of Sciences of the United States of America 108(39): 16229-16234, 2011

X-ray structure of the human protective protein cathepsin A precursor The defective protein in the lysosomal storage disease galactosialidosis. American Journal of Human Genetics 57(4 Suppl): A38, 1995

The crystal structure of DR6 in complex with the amyloid precursor protein provides insight into death receptor activation. Genes and Development 29(8): 785-790, 2015

The crystal structure of calcium-free human m-calpain suggests an electrostatic switch mechanism for activation by calcium. Proceedings of the National Academy of Sciences of the United States of America 97(2): 588-592, 2000

Three-dimensional structure of an independently folded extracellular domain of human amyloid-beta precursor protein. Biochemistry 43(30): 9583-9588, 2004

Structure and activation mechanism of the BBSome membrane protein trafficking complex. Elife 9, 2020

Function from structure? The crystal structure of human phosphatidylethanolamine-binding protein suggests a role in membrane signal transduction. Structure 6(10): 1245-1254, 1998

The structure of the PERK kinase domain suggests the mechanism for its activation. Acta Crystallographica. Section D Biological Crystallography 67(Pt 5): 423-428, 2011

The Structure of Bovine Lysosomal a-Mannosidase Suggests a Novel Mechanism for Low-pH Activation. Journal of Molecular Biology 327(3): 1-44, 2003

The three-dimensional structure of two mutants of the signal transduction protein CheY suggest its molecular activation mechanism. Journal of Molecular Biology 257(1): 116-128, 1996

Cryo-EM structure of NPF-bound human Arp2/3 complex and activation mechanism. Science Advances 6(23): Eaaz7651, 2020

The three-dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC. Cell 70(6): 1035-1048, 1992