scholarly journals Molecular structure and the role of high‐temperature requirement protein 1 in skeletal disorders and cancers

2019 ◽  
Vol 53 (2) ◽  
Author(s):  
Yihe Li ◽  
Jinbo Yuan ◽  
Emel Rothzerg ◽  
Xinghuo Wu ◽  
Huazi Xu ◽  
...  
Author(s):  
Arvind Kumar Gupta ◽  
Debashree Behera ◽  
Balasubramanian Gopal

The crystal structure of Mycobacterium tuberculosis high-temperature requirement A (HtrA) protein was determined at 1.83 Å resolution. This membrane-associated protease is essential for the survival of M. tuberculosis. The crystal structure reveals that interactions between the PDZ domain and the catalytic domain in HtrA lead to an inactive conformation. This finding is consistent with its proposed role as a regulatory protease that is conditionally activated upon appropriate environmental triggers. The structure provides a basis for directed studies to evaluate the role of this essential protein and the regulatory pathways that are influenced by this protease.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mingming Chen ◽  
Shilei Yang ◽  
Yu Wu ◽  
Zirui Zhao ◽  
Xiaohan Zhai ◽  
...  

AbstractAs the life expectancy of the population increases worldwide, cancer is becoming a substantial public health problem. Considering its recurrence and mortality rates, most cancer cases are difficult to cure. In recent decades, a large number of studies have been carried out on different cancer types; unfortunately, tumor incidence and mortality have not been effectively improved. At present, early diagnostic biomarkers and accurate therapeutic strategies for cancer are lacking. High temperature requirement A1 (HtrA1) is a trypsin-fold serine protease that is also a chymotrypsin-like protease family member originally discovered in bacteria and later discovered in mammalian systems. HtrA1 gene expression is decreased in diverse cancers, and it may play a role as a tumor suppressor for promoting the death of tumor cells. This work aimed to examine the role of HtrA1 as a cell type-specific diagnostic biomarker or as an internal and external regulatory factor of diverse cancers. The findings of this study will facilitate the development of HtrA1 as a therapeutic target.


1988 ◽  
Vol 66 (3) ◽  
pp. 563-567 ◽  
Author(s):  
Jerry M. Baskin ◽  
Carol C. Baskin

The peak of germination of autumn-sown seeds of Portulaca oleracea was between 21 May and 21 June, when mean daily maximum and minimum temperatures were 30.7 and 17.4 °C, respectively. Fresh seeds collected in October germinated to 13 and 94% at 30:15 and 35:20 °C thermoperiods, respectively, in light, and to 0% in darkness. Seeds were buried in October 1975 and exhumed in December 1975 through September 1976. In light, exhumed seeds germinated to 69–100% at 30:15 and 35:20 °C,to 1–80% at 20:10 °C, and to 0–52% at 15:6 °C; in darkness they germinated to 5–55% at 30:15 and 35:20 °C and to0% at 20:10 and 15:6 °C. Germination at 20:10 °C did not exceed 50% until mid-April, and it did not exceed 50% at 15:6 °C until June. Fresh seeds were buried at 5, 15:6, 20:10, 25:15, 30:15, and 35:20 °C, and after 0, 1, 3, and 5 months, seeds from each temperature were tested in light and darkness at the five thermoperiods. The minimum temperature at which 50% or more of the seeds germinated in light decreased with an increase in afterripening temperature. The high temperature requirement for complete afterripening and for germination of partially afterripened seeds prevents germination of this summer annual in temperate regions until late spring and early summer.


2021 ◽  
Vol 118 (35) ◽  
pp. e2111257118
Author(s):  
Yuki Toyama ◽  
Robert W. Harkness ◽  
Lewis E. Kay

The human high-temperature requirement A2 (HtrA2) mitochondrial protease is critical for cellular proteostasis, with mutations in this enzyme closely associated with the onset of neurodegenerative disorders. HtrA2 forms a homotrimeric structure, with each subunit composed of protease and PDZ (PSD-95, DLG, ZO-1) domains. Although we had previously shown that successive ligand binding occurs with increasing affinity, and it has been suggested that allostery plays a role in regulating catalysis, the molecular details of how this occurs have not been established. Here, we use cysteine-based chemistry to generate subunits in different conformational states along with a protomer mixing strategy, biochemical assays, and methyl-transverse relaxation optimized spectroscopy–based NMR studies to understand the role of interprotomer allostery in regulating HtrA2 function. We show that substrate binding to a PDZ domain of one protomer increases millisecond-to-microsecond timescale dynamics in neighboring subunits that prime them for binding substrate molecules. Only when all three PDZ-binding sites are substrate bound can the enzyme transition into an active conformation that involves significant structural rearrangements of the protease domains. Our results thus explain why when one (or more) of the protomers is fixed in a ligand-binding–incompetent conformation or contains the inactivating S276C mutation that is causative for a neurodegenerative phenotype in mouse models of Parkinson’s disease, transition to an active state cannot be formed. In this manner, wild-type HtrA2 is only active when substrate concentrations are high and therefore toxic and unregulated proteolysis of nonsubstrate proteins can be suppressed.


Author(s):  
M.I. Ariëns ◽  
V. Chlan ◽  
P. Novák ◽  
L.G.A. van de Water ◽  
A.I. Dugulan ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document