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

Structure
G RudenkoW G Hol

Abstract

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 galactosialidosis. 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. 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 degrees 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. The activation mechanism of HPP is unique among proteases with known structure. ...Continue Reading

References

May 30, 1978·Biochemical and Biophysical Research Communications·D A WengerC Wharton
Apr 1, 1992·Protein Engineering·D L OllisJ Schrag
Mar 5, 1992·Nature·R LüthyD Eisenberg
Jul 31, 1992·Biochimica Et Biophysica Acta·A V Pshezhetsky Wiederschain GYa
Oct 15, 1991·Proceedings of the National Academy of Sciences of the United States of America·J R Winther, P Sørensen
Mar 1, 1991·Acta Crystallographica. Section A, Foundations of Crystallography·T A JonesM Kjeldgaard
Mar 1, 1990·Journal of Molecular Graphics·G Vriend
Jan 1, 1987·The International Journal of Biochemistry·Y Yamamoto, K Nishimura
Apr 28, 1968·Journal of Molecular Biology·B W Matthews
Aug 1, 1982·Proceedings of the National Academy of Sciences of the United States of America·A D'AzzoH Galjaard
Sep 30, 1982·Biochemical and Biophysical Research Communications·F VerheijenH Galjaard
Nov 3, 1995·The Journal of Biological Chemistry·E J BontenA d'Azzo
Sep 20, 1994·Biochemistry·J A EndrizziS J Remington
Jan 13, 1995·The Journal of Biological Chemistry·K ItohY Suzuki
Jan 1, 1994·Methods in Enzymology·S J Remington, K Breddam
Feb 22, 1994·Biochimica Et Biophysica Acta·Y Okamura-OhoJ W Callahan
Jul 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·E T BaldwinJ W Erickson
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Jan 1, 1993·Acta Crystallographica. Section D, Biological Crystallography·V S Lamzin, K S Wilson

❮ Previous
Next ❯

Citations

Jun 1, 1997·Proteins·A V Efimov
May 6, 1998·Protein Science : a Publication of the Protein Society·A R Khan, M N James
Sep 12, 2003·Molecular and Biochemical Parasitology·Fabiola ParussiniJuan José Cazzulo
Aug 28, 2003·Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology·N MiledS Canaan
Nov 26, 1999·Biochimica Et Biophysica Acta·S CanaanC Cambillau
Jun 24, 2011·Chemical Reviews·Jonathan Z Long, Benjamin F Cravatt
Aug 7, 2012·Journal of Medicinal Chemistry·Sven RufThorsten Sadowski
Jan 22, 1998·Proceedings of the National Academy of Sciences of the United States of America·G RudenkoA d'Azzo
Jun 19, 2001·The EMBO Journal·M M Krem, E Di Cera
Mar 19, 2013·Future Medicinal Chemistry·Sven RufThorsten Sadowski
Dec 18, 2013·Cellular and Molecular Life Sciences : CMLS·Erik J BontenAlessandra d'Azzo
Jun 28, 2005·Molecular Genetics and Metabolism·Dongning WangAlessandra d'Azzo
Feb 18, 2014·Biochemical and Biophysical Research Communications·Herman A SchreuderThorsten Sadowski
Aug 1, 2007·Journal of Lipid Research·Raül SantamariaLluïsa Vilageliu
Oct 13, 2018·Protein Science : a Publication of the Protein Society·Polytimi S DimitriouKonstantin Denessiouk
Apr 16, 2004·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Erik J BontenAlessandra D'Azzo
Apr 10, 2014·The Journal of Biological Chemistry·Katarzyna PustelnyGrzegorz Dubin
Aug 16, 2002·The Journal of Biological Chemistry·Maxwell M KremEnrico Di Cera
Aug 22, 2017·Frontiers in Physiology·Cong-Dat PhamYong-Hee P Chun

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.