Roles of the procollagen C-propeptides in health and disease

2019 ◽  
Vol 63 (3) ◽  
pp. 313-323 ◽  
Author(s):  
David J.S. Hulmes
Keyword(s):  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Missense Mutations ◽  
Detailed Model ◽  
Morphogenetic Protein ◽  
Collagen Molecules ◽  
Health And Disease ◽  
The Stability ◽  
New Interactions

AbstractThe procollagen C-propeptides of the fibrillar collagens play key roles in the intracellular assembly of procollagen molecules from their constituent polypeptides chains, and in the extracellular assembly of collagen molecules into fibrils. Here we review recent advances in understanding the molecular mechanisms controlling C-propeptide trimerization which have revealed the importance of inter-chain disulphide bonding and a small number of charged amino acids in the stability and specificity of different types of chain association. We also show how the crystal structure of the complex between the C-propeptide trimer of procollagen III and the active fragment of procollagen C-proteinase enhancer-1 leads to a detailed model for accelerating release of the C-propeptides from procollagen by bone morphogenetic protein-1 and related proteinases. We then discuss the effects of disease-related missense mutations in the C-propeptides in relation to the sites of these mutations in the three-dimensional structure. While in general there is a good correlation between disease severity and structure-based predictions, there are notable exceptions, suggesting new interactions involving the C-propeptides yet to be characterized. Mutations affecting proteolytic release of the C-propeptides from procollagen are discussed in detail. Finally, the roles of recently discovered interaction partners for the C-propeptides are considered during fibril assembly and cross-linking.

Characterization of an A-type cyclin-dependent kinase gene from Dendrobium candidum

Biologia ◽  
2012 ◽  
Vol 67 (2) ◽  
Author(s):  
Gang Zhang ◽  
Chao Song ◽  
Ming-Ming Zhao ◽  
Biao Li ◽  
Shun-Xing Guo
Keyword(s):  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Postembryonic Development ◽  
Kinase Domain ◽  
Dimensional Structure ◽  
Pcr Analysis ◽  
Kinase Gene ◽  
Multiple Sequence ◽  
Dendrobium Candidum ◽  
Rapid Amplification

AbstractCyclin-dependent kinases (CDKs) play an essential role in cell cycle regulation during the embryonic and postembryonic development of organisms. To better understand the molecular mechanisms of CDKs involved in embryogenesis regulation in the endangered medicinal plant Dendrobium candidum Wall. ex Lindl., a 1229-bp full-length cDNA of an A-type CDK gene, Denca;CDKA;1, was identified using 3′ rapid amplification of cDNA end (RACE) PCR. Denca;CDKA;1 was predicted to encode a 294 amino acid residue-long protein of 33.76 kDa with an isoelectric point of 7.72. The deduced Denca;CDKA;1 protein contained a conserved serine/threonine-protein kinase domain (S-TKc) and a canonical cyclinbinding “PSTAIRE” motif. Multiple sequence alignment indicated that members of CDKA family from various plants exhibited a high degree of sequence identity ranging from 82% to 93%. A neighbor-joining phylogenetic tree showed that Denca;CDKA;1 was clustered into the plant group and was distant from the animal and fungal groups. The modeled three-dimensional structure of Denca;CDKA;1 exhibited the similar functional structure of a fold consisting of β-sheets and α-helices joined by discontinuous random coils forming two relatively independent lobes. Quantitative real-time PCR analysis revealed that Denca;CDKA;1 transcripts were the most abundant in protocorm-like bodies with 4.76 fold, followed by that in roots (4.19 fold), seeds (2.57 fold), and stems (1.57 fold). This study characterized the novel Denca;CDKA;1 gene from D. candidum for the first time and the results will be useful for further functional determination of the gene.

scholarly journals Role of the HSP70 Co-Chaperone SIL1 in Health and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1564
Author(s):  
Viraj P. Ichhaporia ◽  
Linda M. Hendershot
Keyword(s):  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Dependent Manner ◽  
Nucleotide Exchange ◽  
Multisystem Disorder ◽  
Nucleotide Exchange Factors ◽  
Precise Understanding ◽  
Health And Disease ◽  
Client Proteins ◽  
Er Homeostasis

Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.

Protein intrachain contact prediction with most interacting residues (MIR)

2014 ◽  
Vol 10 (4) ◽  
Author(s):  
Ruben Acuña ◽  
Zoé Lacroix ◽  
Nikolaos Papandreou ◽  
Jacques Chomilier
Keyword(s):  
Structural Changes ◽  
Hydrophobic Interactions ◽  
Three Dimensional ◽  
Accessible Surface Area ◽  
Dimensional Structure ◽  
Closed Loops ◽  
Folding Process ◽  
Folding Nucleus ◽  
Accessible Surface ◽  
The Stability

AbstractThe transition state ensemble during the folding process of globular proteins occurs when a sufficient number of intrachain contacts are formed, mainly, but not exclusively, due to hydrophobic interactions. These contacts are related to the folding nucleus, and they contribute to the stability of the native structure, although they may disappear after the energetic barrier of transition states has been passed. A number of structure and sequence analyses, as well as protein engineering studies, have shown that the signature of the folding nucleus is surprisingly present in the native three-dimensional structure, in the form of closed loops, and also in the early folding events. These findings support the idea that the residues of the folding nucleus become buried in the very first folding events, therefore helping the formation of closed loops that act as anchor structures, speed up the process, and overcome the Levinthal paradox. We present here a review of an algorithm intended to simulate in a discrete space the early steps of the folding process. It is based on a Monte Carlo simulation where perturbations, or moves, are randomly applied to residues within a sequence. In contrast with many technically similar approaches, this model does not intend to fold the protein but to calculate the number of non-covalent neighbors of each residue, during the early steps of the folding process. Amino acids along the sequence are categorized as most interacting residues (MIRs) or least interacting residues. The MIR method can be applied under a variety of circumstances. In the cases tested thus far, MIR has successfully identified the exact residue whose mutation causes a switch in conformation. This follows with the idea that MIR identifies residues that are important in the folding process. Most MIR positions correspond to hydrophobic residues; correspondingly, MIRs have zero or very low accessible surface area. Alongside the review of the MIR method, we present a new postprocessing method called smoothed MIR (SMIR), which refines the original MIR method by exploiting the knowledge of residue hydrophobicity. We review known results and present new ones, focusing on the ability of MIR to predict structural changes, secondary structure, and the improved precision with the SMIR method.

scholarly journals Nanoparticles Mediated Protein Stability in Comparison with Osmolytes: in vivo Approach

2021 ◽  
Vol 33 (6) ◽  
pp. 1433-1438
Author(s):  
R. Verma ◽  
N. Singh ◽  
P. Chaudhuri (Chattopadhyay)
Keyword(s):  
Gold Nanoparticles ◽  
Dihydrofolate Reductase ◽  
Three Dimensional ◽  
Cellular Level ◽  
Dimensional Structure ◽  
Important Group ◽  
Unfolded State ◽  
The Status ◽  
The Stability

The native three-dimensional structure of protein is quite unstable under critical destabilizing conditions. In order to enhance the stability and activity for a proper folded environment of a protein, many stabilizing materials are added such as nanoparticles and osmolytes to an unfolded state of protein. Osmolytes are the important group of molecules which are engaged by the cell as an adaption in the severe conditions. In this communication, a comparative in vivo study is reported for imparting the status of stability and folding ability of zebrafish dihydrofolate reductase (zDHFR) protein with gold nanoparticles and various osmolytes (glycerol, glucose and betain). Present observations revealed that the interaction of gold nanoparticles (AuNPs) with bacteria at the cellular level helps in maintaining the stability of protein more effectively than osmolytes which could be used for many biological and pharmacological approaches although glycerol as an osmolyte also stabilizes the protein at a significant level.

scholarly journals Two clusters of surface-exposed amino acid residues enable high-affinity binding of retinal degeneration-3 (RD3) protein to retinal guanylyl cyclase

2020 ◽  
Vol 295 (31) ◽  
pp. 10781-10793 ◽  
Author(s):  
Igor V. Peshenko ◽  
Alexander M. Dizhoor
Keyword(s):  
Retinal Degeneration ◽  
Guanylyl Cyclase ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Hek293 Cells ◽  
Dimensional Structure ◽  
Amino Acid Residues ◽  
Retinal Guanylyl Cyclase ◽  
Functional Interface

Retinal degeneration-3 (RD3) protein protects photoreceptors from degeneration by preventing retinal guanylyl cyclase (RetGC) activation via calcium-sensing guanylyl cyclase–activating proteins (GCAP), and RD3 truncation causes severe congenital blindness in humans and other animals. The three-dimensional structure of RD3 has recently been established, but the molecular mechanisms of its inhibitory binding to RetGC remain unclear. Here, we report the results of probing 133 surface-exposed residues in RD3 by single substitutions and deletions to identify side chains that are critical for the inhibitory binding of RD3 to RetGC. We tested the effects of these substitutions and deletions in vitro by reconstituting purified RD3 variants with GCAP1-activated human RetGC1. Although the vast majority of the surface-exposed residues tolerated substitutions without loss of RD3's inhibitory activity, substitutions in two distinct narrow clusters located on the opposite sides of the molecule effectively suppressed RD3 binding to the cyclase. The first surface-exposed cluster included residues adjacent to Leu63 in the loop connecting helices 1 and 2. The second cluster surrounded Arg101 on a surface of helix 3. Single substitutions in those two clusters drastically, i.e. up to 245-fold, reduced the IC50 for the cyclase inhibition. Inactivation of the two binding sites completely disabled binding of RD3 to RetGC1 in living HEK293 cells. In contrast, deletion of 49 C-terminal residues did not affect the apparent affinity of RD3 for RetGC. Our findings identify the functional interface on RD3 required for its inhibitory binding to RetGC, a process essential for protecting photoreceptors from degeneration.

scholarly journals SE-OnionNet: A Convolution Neural Network for Protein–Ligand Binding Affinity Prediction

2021 ◽  
Vol 11 ◽  
Author(s):  
Shudong Wang ◽  
Dayan Liu ◽  
Mao Ding ◽  
Zhenzhen Du ◽  
Yue Zhong ◽  
...  
Keyword(s):  
Neural Network ◽  
Binding Affinity ◽  
Three Dimensional ◽  
Model Performance ◽  
Protein Molecule ◽  
Stochastic Gradient Descent ◽  
Dimensional Structure ◽  
Scoring Functions ◽  
Ligand Complex ◽  
The Stability

Deep learning methods, which can predict the binding affinity of a drug–target protein interaction, reduce the time and cost of drug discovery. In this study, we propose a novel deep convolutional neural network called SE-OnionNet, with two squeeze-and-excitation (SE) modules, to computationally predict the binding affinity of a protein–ligand complex. The OnionNet is used to extract a feature map from the three-dimensional structure of a protein–drug molecular complex. The SE module is added to the second and third convolutional layers to improve the non-linear expression of the network to improve model performance. Three different optimizers, stochastic gradient descent (SGD), Adam, and Adagrad, were also used to improve the performance of the model. A majority of protein–molecule complexes were used for training, and the comparative assessment of scoring functions (CASF-2016) was used as the benchmark. Experimental results show that our model performs better than OnionNet, Pafnucy, and AutoDock Vina. Finally, we chose the macrophage migration inhibitor factor (PDB ID: 6cbg) to test the stability and robustness of the model. We found that the prediction results were not affected by the docking position, and thus, our model is of acceptable robustness.

Topology models of anion exchanger 1 that incorporate the anti-parallel V-shaped motifs found in the EM structureThis paper is one of a selection of papers published in a Special Issue entitled CSBMCB 53rd Annual Meeting — Membrane Proteins in Health and Disease, and has undergone the Journal’s usual peer review process.

2011 ◽  
Vol 89 (2) ◽  
pp. 148-156 ◽  
Author(s):  
Teruhisa Hirai ◽  
Naotaka Hamasaki ◽  
Tomohiro Yamaguchi ◽  
Yohei Ikeda
Keyword(s):  
Anion Exchanger ◽  
Peer Review Process ◽  
Three Dimensional ◽  
Structural Similarity ◽  
Dimensional Structure ◽  
Membrane Bilayer ◽  
Anion Exchanger 1 ◽  
Advantages And Disadvantages ◽  
Health And Disease ◽  
Selection Of

We recently published the three-dimensional structure of the membrane domain of human erythrocyte anion exchanger 1 (AE1) at 7.5 Å resolution, solved by electron crystallography. The structure exhibited distinctive anti-parallel V-shaped motifs, which protrude from the membrane bilayer on both sides. Similar motifs exist in the previously reported structure of a bacterial chloride channel (ClC)-type protein. Here, we propose two topology models of AE1 that reflect the anti-parallel V-shaped structural motifs. One is assumed to have structural similarity with the ClC protein and the other is only assumed to have internal repeats, as is often the case with transporters. Both models are consistent with most topological results reported thus far for AE1, each having advantages and disadvantages.

scholarly journals Nonorthogonal Aerial Optoelectronic Platform Based on Triaxial and Control Method Designed for Image Sensors

Sensors ◽  
2019 ◽  
Vol 20 (1) ◽  
pp. 10
Author(s):  
Quanchao Li ◽  
Shuyan Xu ◽  
Yulei Xu ◽  
Lei Li ◽  
Liu Zhang
Keyword(s):  
Optical Sensors ◽  
Control Method ◽  
Three Dimensional ◽  
Voice Coil Motor ◽  
Image Sensor ◽  
Dimensional Structure ◽  
Internal Space ◽  
Drive Control ◽  
The Stability ◽  
Better Than

A traditional aerial optoelectronic platform consists of inside and outside multilayer gimbals, while an internal gimbal and drive components occupy the internal space where optical sensors are located. In order to improve the replaceability of optical sensors and to increase their available space, this paper introduces a nonorthogonal aerial optoelectronic platform based on three axes; we carried out research on its drive control method. A three-dimensional structure of an aerial optoelectronic platform was designed. A noncontact drive of a linear voice coil motor was introduced, and a drive control scheme of a proportional integral and a disturbance observer was adopted. Finally, simulations and experiments were carried out. Results showed that the aerial optoelectronic platform could effectively release three times the image sensor space, and the servo bandwidth was 60.2 Hz, which was much better than that of traditional two-axis and four-gimbal platforms. The stability accuracy of the system reached 4.9958 micron rad, which was obviously better than that of traditional gimbals. This paper provides a reference for the design of new optoelectronic platforms.

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