helical domain
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2022 ◽  
Author(s):  
Young-Hee Shin ◽  
Hyunjun Yang

Systematic incorportation of ring-constrained β- and γ-amino acid residues to α-helix mimetics engenders stable helical secondary structures. In this paper, functional α/β/γ-helical peptidomimetics were explored for the mimicry of BH3...


FEBS Journal ◽  
2021 ◽  
Author(s):  
Dick J Sjöström ◽  
Camilla Mohlin ◽  
Elena Ambrosetti ◽  
Scott J Garforth ◽  
Ana I Teixeira ◽  
...  

2021 ◽  
Vol 11 (10) ◽  
pp. 1328
Author(s):  
Eva Bagyinszky ◽  
Gaik-Siew Ch’ng ◽  
Mei-Yan Chan ◽  
Seong Soo A. An ◽  
SangYun Kim

Presenilin-1 (PSEN1) is one of the causative genes for early onset Alzheimer’s disease (EOAD). Recently, emerging studies have reported several novel PSEN1 mutations among Asians. In this study, a PSEN1 Val96Phe mutation was discovered in two siblings from Malaysia with a strong family history of disease. This is the second report of PSEN1 Val96Phe mutation among EOAD patients in Asia and in the world. Patients presented symptomatic changes in their behaviors and personality, such as apathy and withdrawal in their 40s. Previous cellular studies with COS1 cell lines revealed the mutation increased the amyloid-β42 (Aβ42) productions. In the present study, whole-exome sequencing was performed on the two siblings with EOAD, and they were analyzed against the virtual panel of 100 genes from various neurodegenerative diseases. In silico modeling was also performed on PSEN1 Val96Phe mutation. This mutation was located on the first transmembrane helix of PSEN1 protein, resulting significant intramolecular stresses in the helices. This helical domain would play a significant role in γ-secretase cleavage for the increased Aβ42 productions. Several other adjacent mutations were reported in this helical domain, including Ile83Thr or Val89Leu. Our study suggested that perturbations in TMI-HLI-TMII regions could also be associated with C-terminal fragment accumulation of APP and enhanced amyloid productions.


2021 ◽  
Vol 11 (6) ◽  
pp. 579
Author(s):  
Malorie Blancard ◽  
Zahia Touat-Hamici ◽  
Yuriana Aguilar-Sanchez ◽  
Liheng Yin ◽  
Guy Vaksmann ◽  
...  

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is triggered by exercise or acute emotion in patients with normal resting electrocardiogram. The major disease-causing gene is RYR2, encoding the cardiac ryanodine receptor (RyR2). We report a novel RYR2 variant, p.Asp3291Val, outside the four CPVT mutation hotspots, in three CPVT families with numerous sudden deaths. This missense variant was first identified in a four-generation family, where eight sudden cardiac deaths occurred before the age of 30 in the context of adrenergic stress. All affected subjects harbored at least one copy of the RYR2 variant. Three affected sisters were homozygous for the variant. The same variant was found in two additional CPVT families. It is located in the helical domain 2 and changes a negatively charged amino acid widely conserved through evolution. Functional analysis of D3291V channels revealed a normal response to cytosolic Ca2+, a markedly reduced luminal Ca2+ sensitivity and, more importantly, an absence of normal response to 8-bromo-cAMP and forskolin stimulation in both transfected HEK293 and HL-1 cells. Our data support that the D3291V-RyR2 is a loss-of-function RyR2 variant responsible for an atypical form of CPVT inducing a mild dysfunction in basal conditions but leading potentially to fatal events through its unresponsiveness to adrenergic stimulation.


2020 ◽  
Vol 11 ◽  
Author(s):  
Jessica N. Ross ◽  
Francisco R. Fields ◽  
Veronica R. Kalwajtys ◽  
Alejandro J. Gonzalez ◽  
Samantha O’Connor ◽  
...  

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Junqiao Jia ◽  
Eva Absmeier ◽  
Nicole Holton ◽  
Agnieszka J. Pietrzyk-Brzezinska ◽  
Philipp Hackert ◽  
...  

Abstract The ASCC3 subunit of the activating signal co-integrator complex is a dual-cassette Ski2-like nucleic acid helicase that provides single-stranded DNA for alkylation damage repair by the α-ketoglutarate-dependent dioxygenase AlkBH3. Other ASCC components integrate ASCC3/AlkBH3 into a complex DNA repair pathway. We mapped and structurally analyzed interacting ASCC2 and ASCC3 regions. The ASCC3 fragment comprises a central helical domain and terminal, extended arms that clasp the compact ASCC2 unit. ASCC2–ASCC3 interfaces are evolutionarily highly conserved and comprise a large number of residues affected by somatic cancer mutations. We quantified contributions of protein regions to the ASCC2–ASCC3 interaction, observing that changes found in cancers lead to reduced ASCC2–ASCC3 affinity. Functional dissection of ASCC3 revealed similar organization and regulation as in the spliceosomal RNA helicase Brr2. Our results delineate functional regions in an important DNA repair complex and suggest possible molecular disease principles.


Life Sciences ◽  
2020 ◽  
pp. 118759
Author(s):  
Safoura Ghalamkari ◽  
Shahryar Alavi ◽  
Hamidreza Mianesaz ◽  
Farinaz Khosravian ◽  
Amir Bahreini ◽  
...  
Keyword(s):  

2020 ◽  
Author(s):  
Pooja Asthana ◽  
Dhirendra Singh ◽  
Jan Skov Pedersen ◽  
Mikko J. Hynönen ◽  
Ramita Sulu ◽  
...  

AbstractTuberculosis (Tb), caused by Mycobacterium tuberculosis (Mtb), is responsible for more than a million deaths annually. In the latent phase of infection, Mtb uses lipids as the source of carbon and energy for its survival. The lipid molecules are transported across the cell wall via multiple transport systems. One such set of widely present and less-studied transporters is the Mammalian-cell-entry (Mce) complexes. Here, we report the properties of the substrate-binding proteins (SBPs; MceA-F) of the Mce1 and Mce4 complexes from Mtb which are responsible for the import of mycolic acid/fatty acids, and cholesterol respectively. MceA-F are composed of four domains namely, transmembrane, MCE, helical and tail domains. Our studies show that MceA-F are predominantly monomeric when purified individually and do not form homohexamers unlike the reported homologs (MlaD, PqiB and LetB) from other prokaryotes. The crystal structure of MCE domain of Mtb Mce4A (MtMce4A39-140) determined at 2.9 Å shows the formation of an unexpected domain-swapped dimer in the crystals. Further, the purification and small-angle X-ray scattering (SAXS) analysis on MtMce1A, MtMce4A and their domains suggest that the helical domain requires hydrophobic interactions with the detergent molecules for its stability. Combining all the experimental data, we propose a heterohexameric arrangement of MtMceA-F SBPs, where the soluble MCE domain of the SBPs would remain in the periplasm with the helical domain extending to the lipid layer forming a hollow channel for the transport of lipids across the membranes. The tail domain would reach the cell surface assisting in lipid recognition and binding.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuliya K. Agapova ◽  
Dmitry A. Altukhov ◽  
Vladimir I. Timofeev ◽  
Victor S. Stroylov ◽  
Vitaly S. Mityanov ◽  
...  

Abstract Here we report bisphenol derivatives of fluorene (BDFs) as a new type of chemical probes targeting a histone-like HU protein, a global regulator of bacterial nucleoids, via its dimerization interface perturbation. BDFs were identified by virtual screening and molecular docking that targeted the core of DNA-binding β-saddle-like domain of the HU protein from Spiroplasma melliferum. However, NMR spectroscopy, complemented with molecular dynamics and site-directed mutagenesis, indicated that the actual site of the inhibitors’ intervention consists of residues from the α-helical domain of one monomer and the side portion of the DNA-binding domain of another monomer. BDFs inhibited DNA-binding properties of HU proteins from mycoplasmas S. melliferum, Mycoplasma gallicepticum and Escherichia coli with half-maximum inhibitory concentrations in the range between 5 and 10 µM. In addition, BDFs demonstrated antimicrobial activity against mycoplasma species, but not against E. coli, which is consistent with the compensatory role of other nucleoid-associated proteins in the higher bacteria. Further evaluation of antimicrobial effects of BDFs against various bacteria and viruses will reveal their pharmacological potential, and the allosteric inhibition mode reported here, which avoids direct competition for the binding site with DNA, should be considered in the development of small molecule inhibitors of nucleoid-associated proteins as well as other types of DNA-binding multimeric proteins.


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