Structural and functional analysis of HtrA1 and its subdomains

Structure
Charles EigenbrotDaniel Kirchhofer

Abstract

The homotrimeric human serine protease HtrA1 is homologous to bacterial HtrA proteases regarding the trypsin-like catalytic and PDZ domains but differs by the presence of an N-terminal domain with IGFBP and Kazal homology. The crystal structures and SAXS analysis presented herein reveal the rare tandem of IGFBP- and Kazal-like modules, a protease active site that adopts a competent conformation in the absence of substrate or inhibitor and a model for the intact protein in solution. Highly sensitive enzymatic assays and binding studies demonstrate that the N-terminal tandem has no apparent effect on protease activity, and in accordance with the structure-based predictions, neither the IGFBP- nor Kazal-like module retains the function of their prototype proteins. Our structures of the unliganded HtrA1 active site suggest two-state equilibrium and a "conformational selection" model, in which substrate binds to the active conformer.

References

Mar 10, 1995·Journal of Molecular Biology·B ArnouxA Ducruix
Aug 23, 1996·The Journal of Biological Chemistry·P LassalleA B Tonnel
Sep 10, 2002·Journal of Molecular Biology·Ana L CarvalhoMaria J Romão
Nov 1, 2002·Molecular Cell·Tim ClausenMichael Ehrmann
Sep 27, 2003·The Journal of Biological Chemistry·L Miguel MartinsJulian Downward
Feb 20, 2004·Development·Chio OkaMasashi Kawaichi
Apr 23, 2004·The Biochemical Journal· MurwantokoMasashi Kawaichi
Jun 23, 2004·Development, Growth & Differentiation·Jiraporn TocharusMasashi Kawaichi
Jun 7, 2005·Trends in Endocrinology and Metabolism : TEM·Leon A BachRaymond S Norton
Jun 10, 2005·Journal of Biochemistry and Molecular Biology·Dong Young Kim, Kyeong Kyu Kim
Oct 6, 2005·The Biochemical Journal·Daniel J D JohnsonJames A Huntington
Dec 27, 2005·The Journal of Biological Chemistry·Sandra GrauMichael Ehrmann
Aug 23, 2006·Proceedings of the National Academy of Sciences of the United States of America·Tomasz SitarTad A Holak
Oct 21, 2006·Science·Andrew DewanJosephine Hoh
Nov 6, 2007·Cell·Jungsan SohnRobert T Sauer
Dec 25, 2007·The Journal of Biological Chemistry·Kristen D HadfieldAnn E Canfield
Sep 16, 2008·Trends in Biochemical Sciences·Kenneth P HolbournBernard Perbal
Sep 1, 1948·Journal of the American Chemical Society·L A KAZALR A BRAHINSKY
Nov 4, 2008·Biological Chemistry·James A Huntington
Apr 24, 2009·The New England Journal of Medicine·Kenju HaraOsamu Onodera
Apr 24, 2009·Protein Science : a Publication of the Protein Society·Glen SpraggonScott A Lesley
Aug 12, 2009·Proceedings of the National Academy of Sciences of the United States of America·Gordon G HammesTerrence G Oas
Oct 21, 2009·Nature Chemical Biology·David D BoehrPeter E Wright
Aug 27, 2010·The Journal of Biological Chemistry·Jungsan SohnRobert T Sauer
Feb 8, 2011·Nature Structural & Molecular Biology·Linda TruebesteinMichael Ehrmann
Feb 18, 2011·Nature Reviews. Molecular Cell Biology·Tim ClausenMichael Ehrmann
Jul 6, 2011·Trends in Biotechnology·David W Gohara, Enrico Di Cera

❮ Previous
Next ❯

Citations

May 2, 2013·Acta Crystallographica. Section D, Biological Crystallography·Wei SunWeimin Gong
Aug 2, 2012·Cell Stress & Chaperones·Dorota Zurawa-JanickaBarbara Lipinska
Dec 26, 2015·Biochimica Et Biophysica Acta·Miroslaw JarzabBarbara Lipinska
Aug 28, 2015·Human Molecular Genetics·Ulrike FriedrichBernhard H F Weber
Oct 6, 2015·Nature Chemical Biology·Simon PoepselMichael Ehrmann
Dec 1, 2014·Journal of Experimental Orthopaedics·Peter J Roughley, John S Mort
Mar 19, 2013·The American Journal of Pathology·André Nicki Tiaden, Peter James Richards
Nov 15, 2016·Laboratory Investigation; a Journal of Technical Methods and Pathology·Tsz Kin NgChi Pui Pang
Jul 22, 2017·PloS One·Gladys FilliatPeter J Richards
Dec 23, 2017·Scientific Reports·Oriane GlobusRina Rosin-Arbesfeld
Oct 11, 2017·Journal of Molecular Cell Biology·Maximilian J GerhardtSarah Melissa P Jacobo
Sep 11, 2018·Acta Crystallographica. Section D, Structural Biology·Khundrakpam Herojit SinghBichitra Kumar Biswal
Aug 15, 2014·Stroke; a Journal of Cerebral Circulation·Hiroaki NozakiOsamu Onodera
Oct 13, 2017·Cell Death & Disease·Matthew MerskiSandra Macedo-Ribeiro
May 1, 2019·The Biochemical Journal·Raghupathi KummariKakoli Bose
Feb 11, 2020·Acta Crystallographica. Section D, Structural Biology·Emma Ruoqi XuMarko Hyvönen
Sep 20, 2015·The Biochemical Journal·Claudio CiferriDaniel Kirchhofer
Aug 2, 2014·Current Protocols in Protein Science·Wendy Sandoval
Apr 23, 2017·Medical Science Monitor : International Medical Journal of Experimental and Clinical Research·Dapeng LiYan Wu
Nov 3, 2017·Scientific Reports·Alvaro Cortes CabreraPaula Petrone
Jun 26, 2015·PloS One·Przemyslaw GlazaBarbara Lipinska
Aug 7, 2017·CNS Neuroscience & Therapeutics·Ilaria Di DonatoMaria Teresa Dotti
Apr 30, 2020·Proceedings of the National Academy of Sciences of the United States of America·Irene TomJennie R Lill
Jul 21, 2017·Cellular and Molecular Life Sciences : CMLS·Åsa Fex SvenningsenEirikur Benedikz
Dec 10, 2020·Circulation Research·Md Mehedi HassanSeong-Tshool Hong
Oct 29, 2020·Chinese Medical Journal·Jing-Yi LiuMing Yao
Sep 11, 2019·Biochimie·Peter GoettigViktor Magdolen
May 7, 2021·Journal of the American Society of Nephrology : JASN·Laith Farah Al-RabadiLaurence H Beck
Jul 25, 2021·Journal of Stroke and Cerebrovascular Diseases : the Official Journal of National Stroke Association·Can Ebru Bekircan-KurtMehmet Akif Topcuoglu
Aug 14, 2020·ACS Chemical Biology·Ho Yeon NamJiyoun Lee

❮ 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.