Substrate Sequence Determines Catalytic Activities, Domain-Binding Preferences, and Allosteric Mechanisms in Pin1

The Journal of Physical Chemistry. B
Mohamed MominDonald Hamelberg

Abstract

Pin1 is a unique phosphorylation-dependent peptidyl-prolyl isomerase that regulates diverse subcellular processes and an important potential therapeutic target. Functional mechanisms of Pin1 are complicated because of the two-domain structural organization: the catalytic domain both binds the specific pSer/Thr-Pro motif and catalyzes the cis/trans isomerization, whereas the WW domain can only bind the trans configuration and is speculated to be responsible for substrate-binding specificity. Numerous studies of Pin1 have led to two divergent conclusions on the functional role of the WW domain. One opinion states that the WW domain is an allosteric effector, and substrate binding to this domain modulates the binding and catalysis in the distal catalytic domain. The other opinion, however, argues that the WW domain does not have any allosteric role. Here, using molecular dynamics and binding free-energy calculations, we examine catalysis and allosteric mechanisms in Pin1 under various substrate- and WW-binding conditions. Our results reveal a strong substrate sequence dependency of catalysis, domain-binding preferences, and allosteric outputs in Pin1. Importantly, we show that the different opinions about the WW domain can be unif...Continue Reading

References

Jan 1, 1984·European Biophysics Journal : EBJ·A Cooper, D T Dryden
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
May 1, 1965·Journal of Molecular Biology·J MONODJ P CHANGEUX
Apr 15, 2004·Trends in Biochemical Sciences·Kun Ping Lu
Sep 24, 2004·Proteins·K GunasekaranRuth Nussinov
Aug 31, 2006·Bioinformatics·Barry J GrantLeo S D Caves
Sep 20, 2007·Nature Reviews. Molecular Cell Biology·Kun Ping Lu, Xiao Zhen Zhou
Oct 9, 2007·The Journal of Physical Chemistry. B·Chunhu TanRay Luo
Jul 13, 2011·Proceedings of the National Academy of Sciences of the United States of America·Andrew T NamanjaJeffrey W Peng
Dec 25, 2012·Journal of Chemical Theory and Computation·T SteinbrecherD A Case
Feb 15, 2013·Frontiers in Physiology·Brendan T InnesDavid W Litchfield
Apr 16, 2013·Cell·Ruth Nussinov, Chung-Jung Tsai
Feb 12, 2014·PLoS Computational Biology·Chung-Jung Tsai, Ruth Nussinov
Apr 1, 2014·Current Opinion in Cell Biology·James W WislerRobert J Lefkowitz
Dec 11, 2014·BMC Bioinformatics·Lars SkjærvenBarry J Grant
Dec 30, 2014·Structure·Jingjing GuoHuan-Xiang Zhou
Jan 15, 2015·Biochimica Et Biophysica Acta·Jane A DriverKun Ping Lu
Mar 22, 2016·Journal of Molecular Biology·Timo EichnerDorothee Kern
Apr 14, 2016·Proceedings of the National Academy of Sciences of the United States of America·Urmi DoshiDonald Hamelberg
Apr 14, 2016·Chemical Reviews·Jeffrey R WagnerRommie E Amaro
Apr 15, 2016·The Journal of Physical Chemistry. B·Arghya Barman, Donald Hamelberg
Jun 3, 2016·PLoS Computational Biology·Jin Liu, Ruth Nussinov
Jun 4, 2016·Nature Reviews. Cancer·Xiao Zhen Zhou, Kun Ping Lu
Jan 24, 2018·The Journal of Physical Chemistry. B·Paul CampitelliS Banu Ozkan
Apr 3, 2018·Biochemical and Biophysical Research Communications·Masafumi HidakaTakafumi Uchida

❮ Previous
Next ❯

Citations

Nov 22, 2018·Frontiers in Oncology·Yew Mun Lee, Yih-Cherng Liou
Apr 17, 2020·Frontiers in Cell and Developmental Biology·Wenchen PuYong Peng
Dec 7, 2018·Biochemistry·Dinusha JinasenaNicholas C Fitzkee
Dec 4, 2019·Accounts of Chemical Research·Xin-Qiu Yao, Donald Hamelberg
Jun 30, 2018·Journal of Chemical Information and Modeling·Xin-Qiu YaoDonald Hamelberg

❮ 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.