scholarly journals Distribution of disease-causing germline mutations in coiled-coils suggests essential role of their N-terminal region

2020 ◽  
Author(s):  
Zsofia E. Kalman ◽  
Bálint Mészáros ◽  
Zoltán Gáspári ◽  
Laszlo Dobson
Keyword(s):  
Essential Role ◽  
Coiled Coil ◽  
Germline Mutations ◽  
Coiled Coils ◽  
Helical Structures ◽  
Diverse Range ◽  
Human Proteins ◽  
Range Of Functions ◽  
Functional Explanations

AbstractNext-generation sequencing resulted in the identification of a huge number of naturally occurring variations in human proteins. The correct interpretation of the functional effects of these variations necessitates the understanding of how they modulate protein structure. Coiled-coils are α-helical structures responsible for a diverse range of functions, but most importantly, they facilitate the structural organization of macromolecular scaffolds via oligomerization. In this study, we analyzed a comprehensive set of disease-associated germline mutations in coiled-coil structures. Our results highlight the essential role of residues near the N-terminal part of coiled-coil regions, possibly critical for superhelix assembly and folding in some cases. We also show that coiled-coils of different oligomerization states exhibit characteristically distinct patterns of disease-causing mutations. Our study provides structural and functional explanations on how disease emerges through the mutation of these structural motifs.

scholarly journals Distribution of disease-causing germline mutations in coiled-coils implies an important role of their N-terminal region

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zsofia E. Kalman ◽  
Bálint Mészáros ◽  
Zoltán Gáspári ◽  
Laszlo Dobson
Keyword(s):  
Coiled Coil ◽  
Germline Mutations ◽  
Coiled Coils ◽  
Helical Structures ◽  
Diverse Range ◽  
Naturally Occurring ◽  
Human Proteins ◽  
Range Of Functions ◽  
Functional Explanations

Abstract Next-generation sequencing resulted in the identification of a huge number of naturally occurring variations in human proteins. The correct interpretation of the functional effects of these variations necessitates the understanding of how they modulate protein structure. Coiled-coils are α-helical structures responsible for a diverse range of functions, but most importantly, they facilitate the structural organization of macromolecular scaffolds via oligomerization. In this study, we analyzed a comprehensive set of disease-associated germline mutations in coiled-coil structures. Our results suggest an important role of residues near the N-terminal part of coiled-coil regions, possibly critical for superhelix assembly and folding in some cases. We also show that coiled-coils of different oligomerization states exhibit characteristically distinct patterns of disease-causing mutations. Our study provides structural and functional explanations on how disease emerges through the mutation of these structural motifs.

scholarly journals ARCIMBOLDOon coiled coils

2018 ◽  
Vol 74 (3) ◽  
pp. 194-204 ◽  
Author(s):  
Iracema Caballero ◽  
Massimo Sammito ◽  
Claudia Millán ◽  
Andrey Lebedev ◽  
Nicolas Soler ◽  
...  
Keyword(s):  
Coiled Coil ◽  
Coiled Coils ◽  
Translational Symmetry ◽  
Command Line ◽  
Phase Problem ◽  
Final Solution ◽  
Resolution Limit ◽  
Helical Structures ◽  
Small Model ◽  
Test Pool

ARCIMBOLDOsolves the phase problem by combining the location of small model fragments usingPhaserwith density modification and autotracing usingSHELXE. Mainly helical structures constitute favourable cases, which can be solved using polyalanine helical fragments as search models. Nevertheless, the solution of coiled-coil structures is often complicated by their anisotropic diffraction and apparent translational noncrystallographic symmetry. Long, straight helices have internal translational symmetry and their alignment in preferential directions gives rise to systematic overlap of Patterson vectors. This situation has to be differentiated from the translational symmetry relating different monomers.ARCIMBOLDO_LITEhas been run on single workstations on a test pool of 150 coiled-coil structures with 15–635 amino acids per asymmetric unit and with diffraction data resolutions of between 0.9 and 3.0 Å. The results have been used to identify and address specific issues when solving this class of structures usingARCIMBOLDO. Features fromPhaserv.2.7 onwards are essential to correct anisotropy and produce translation solutions that will pass the packing filters. As the resolution becomes worse than 2.3 Å, the helix direction may be reversed in the placed fragments. Differentiation between true solutions and pseudo-solutions, in which helix fragments were correctly positioned but in a reverse orientation, was found to be problematic at resolutions worse than 2.3 Å. Therefore, after every new fragment-placement round, complete or sparse combinations of helices in alternative directions are generated and evaluated. The final solution is once again probed by helix reversal, refinement and extension. To conclude, density modification andSHELXEautotracing incorporating helical constraints is also exploited to extend the resolution limit in the case of coiled coils and to enhance the identification of correct solutions. This study resulted in a specialized mode withinARCIMBOLDOfor the solution of coiled-coil structures, which overrides the resolution limit and can be invoked from the command line (keyword coiled_coil) orARCIMBOLDO_LITEtask interface inCCP4i.

scholarly journals The Membrane Associated RING-CH Proteins: A Family of E3 Ligases with Diverse Roles through the Cell

2014 ◽  
Vol 2014 ◽  
pp. 1-23 ◽  
Author(s):  
Tasleem Samji ◽  
Soonwook Hong ◽  
Robert E. Means
Keyword(s):  
Signal Transduction ◽  
Dna Repair ◽  
Essential Role ◽  
Proteolytic Degradation ◽  
Diverse Range ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Range Of Functions ◽  
Membrane Bound ◽  
Lines Of Evidence

Since the discovery that conjugation of ubiquitin to proteins can drive proteolytic degradation, ubiquitination has been shown to perform a diverse range of functions in the cell. It plays an important role in endocytosis, signal transduction, trafficking of vesicles inside the cell, and even DNA repair. The process of ubiquitination-mediated control has turned out to be remarkably complex, involving a diverse array of proteins and many levels of control. This review focuses on a family of structurally related E3 ligases termed the membrane-associated RING-CH (MARCH) ubiquitin ligases, which were originally discovered as structural homologs to the virals E3s, K3, and K5 from Kaposi’s sarcoma-associated herpesvirus (KSHV). These proteins contain a catalytic RING-CH finger and are typically membrane-bound, with some having up to 14 putative transmembrane domains. Despite several lines of evidence showing that the MARCH proteins play a complex and essential role in several cellular processes, this family remains understudied.

scholarly journals Structural and Functional Analysis of Essential pre-mRNA Splicing Factor Prp19p

2005 ◽  
Vol 25 (1) ◽  
pp. 451-460 ◽  
Author(s):  
Melanie D. Ohi ◽  
Craig W. Vander Kooi ◽  
Joshua A. Rosenberg ◽  
Liping Ren ◽  
Justin P. Hirsch ◽  
...  
Keyword(s):  
Functional Data ◽  
Coiled Coil ◽  
Single Copy ◽  
Coiled Coils ◽  
Binding Partner ◽  
Central Stalk ◽  
Interaction Surface

ABSTRACT U-box-containing Prp19p is an integral component of the Prp19p-associated complex (the nineteen complex, or NTC) that is essential for activation of the spliceosome. Prp19p makes numerous protein-protein contacts with other NTC components and is required for NTC stability. Here we show that Prp19p forms a tetramer in vitro and in vivo and we map the domain required for its oligomerization to a central tetrameric coiled-coil. Biochemical and in vivo analyses are consistent with Prp19p tetramerization providing an interaction surface for a single copy of its binding partner, Cef1p. Electron microscopy showed that the isolated Prp19p tetramer is an elongated particle consisting of four globular WD40 domains held together by a central stalk consisting of four N-terminal U-boxes and four coiled-coils. These structural and functional data provide a basis for understanding the role of Prp19p as a key architectural component of the NTC.

scholarly journals A Role for the Sendai Virus P Protein Trimer in RNA Synthesis

1998 ◽  
Vol 72 (5) ◽  
pp. 4274-4280 ◽  
Author(s):  
Joseph Curran
Keyword(s):  
Amino Acids ◽  
Mammalian Cells ◽  
Essential Role ◽  
Rna Synthesis ◽  
Sendai Virus ◽  
Coiled Coil ◽  
The Third ◽  
P Protein ◽  
P Proteins

ABSTRACT The SeV P protein is found as a homotrimer (P3) when it is expressed in mammalian cells, and trimerization is mediated by a predicted coiled-coil motif which maps within amino acids (aa) 344 to 411 (the BoxA region). The bacterially expressed protein also appears to be trimeric, apparently precluding a role for phosphorylation in the association of the P monomers. I have examined the role of P trimerization both in the protein’s interaction with the nucleocapsid (N:RNA) template and in the protein’s function on the template during RNA synthesis. As with the results of earlier experiments (32), I found that both the BoxA and BoxC (aa 479 to 568) regions were required for stable binding of P to the N:RNA. Binding was also observed with P proteins containing less than three BoxC regions, suggesting that trimerization may be required to permit contacts between multiple BoxC regions and the N:RNA. However, these heterologous trimers failed to function in viral RNA synthesis, indicating that the third C-terminal leg of the trimer plays an essential role in P function on the template. We speculate that this function may involve the movement of P (and possibly the polymerase complex) on the template and the maintenance of processivity.

scholarly journals Separation of coiled-coil structures in lamin A/C is required for elongation of the filament

2020 ◽  
Author(s):  
Jinsook Ahn ◽  
Soyeon Jeong ◽  
So-mi Kang ◽  
Inseong Jo ◽  
Bum-Joon Park ◽  
...  
Keyword(s):  
Structural Transition ◽  
Coiled Coil ◽  
Binding Mode ◽  
Coiled Coils ◽  
Lamin A ◽  
Structural Elements ◽  
Mutant Proteins ◽  
Biochemical Effects ◽  
Insight Into

AbstractIntermediate filaments (IFs) commonly have structural elements of a central α-helical coiled-coil domain consisting of coil 1a, coil 1b, coil 2, and their flanking linkers. Recently, crystal structure of a long lamin A/C fragment was determined and showed detailed features of a tetrameric unit. The structure further suggested a new binding mode between tetramers, designated eA22, where a parallel overlap of coil 1a and coil 2 is the key interaction. In this study, we investigated the biochemical effects of genetic mutations causing human diseases, focusing on the eA22 interaction. The mutant proteins exhibited either weakened or augmented interactions between coil 1a and coil 2. The ensuing biochemical results indicated that the interaction requires the separation of the coiled-coils in N-terminal of coil 1a and C-terminal of coil 2, coupled with the structural transition in the central α-helical rod domain. This study provides insight into the role of coil 1a as a molecular regulator in elongation of the IF proteins.

scholarly journals Essential Role of Coiled Coils for Aggregation and Activity of Q/N-Rich Prions and PolyQ Proteins

Cell ◽  
2010 ◽  
Vol 143 (7) ◽  
pp. 1121-1135 ◽  
Author(s):  
Ferdinando Fiumara ◽  
Luana Fioriti ◽  
Eric R. Kandel ◽  
Wayne A. Hendrickson
Keyword(s):  
Essential Role ◽  
Coiled Coils

scholarly journals Combined molecular/continuum modeling reveals the role of friction during fast unfolding of coiled-coil proteins

Soft Matter ◽  
2019 ◽  
Vol 15 (24) ◽  
pp. 4961-4975 ◽  
Author(s):  
Alejandro Torres-Sánchez ◽  
Juan M. Vanegas ◽  
Prashant K. Purohit ◽  
Marino Arroyo
Keyword(s):  
Protein Unfolding ◽  
Coiled Coil ◽  
Coiled Coils ◽  
Hydrodynamic Interactions ◽  
Continuum Modeling

Coiled-coils are filamentous proteins capable of reversible unfolding. We show that hydrodynamic interactions with the solvent, usually neglected in theories of protein unfolding, are critical to understand their unfolding at high rates.

scholarly journals Ccdc38 is required for sperm flagellum biogenesis and male fertility in mouse

2022 ◽  
Author(s):  
Ruidan Zhang ◽  
Wei Li ◽  
Li Yuan ◽  
Fei Gao ◽  
Bingbing Wu ◽  
...  
Keyword(s):  
Male Infertility ◽  
Male Fertility ◽  
Essential Role ◽  
Coiled Coil ◽  
Male Mice ◽  
Sperm Tail ◽  
Mouse Sperm ◽  
Sperm Flagellum ◽  
Coiled Coil Domain

Sperm flagellum is essential for male fertility, defects in flagellum biogenesis are associated with male infertility. Deficiency of CCDC42 is associated with malformation of the mouse sperm flagella. Here, we find that the testis-specific expressed protein CCDC38 (coiled coil domain containing 38) interacts with CCDC42 and localizes on manchette and sperm tail during spermiogenesis. Inactivation of CCDC38 in male mice results in distorted manchette, multiple morphological abnormalities of the flagella (MMAF) of spermatozoa, and eventually male sterility. Furthermore, we find that CCDC38 interacts with intra-flagellar transport protein 88 (IFT88) as well as the outer dense fibrous 2 (ODF2), and its depletion reduces the transportation of ODF2 to flagellum. Altogether, our results uncover the essential role of CCDC38 during sperm flagellum biogenesis, and suggesting the defects of these genes might be associated with male infertility in human being.

scholarly journals The clear and dark sides of water: influence on the coiled coil folding domain

2016 ◽  
Vol 7 (3) ◽  
pp. 189-195 ◽  
Author(s):  
Tamás Vajda ◽  
András Perczel
Keyword(s):  
Water Molecule ◽  
Essential Role ◽  
Polypeptide Chain ◽  
Coiled Coil ◽  
Type Ii ◽  
Coiled Coil Domain ◽  
Coil Structure ◽  
Influence Of Water ◽  
The Stability

AbstractThe essential role of water in extra- and intracellular coiled coil structures of proteins is critically evaluated, and the different protein types incorporating coiled coil units are overviewed. The following subjects are discussed: i) influence of water on the formation and degradation of the coiled coil domain together with the stability of this conformer type; ii) the water’s paradox iii) design of coiled coil motifs and iv) expert opinion and outlook is presented. The clear and dark sides refer to the positive and negative aspects of the water molecule, as it may enhance or inhibit a given folding event. This duplicity can be symbolized by the Roman ‘Janus-face’ which means that water may facilitate and stimulate coiled coil structure formation, however, it may contribute to the fatal processes of oligomerization and amyloidosis of the very same polypeptide chain.

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