scholarly journals Dnm1 forms spirals that are structurally tailored to fit mitochondria

2005 ◽  
Vol 170 (7) ◽  
pp. 1021-1027 ◽  
Author(s):  
Elena Ingerman ◽  
Edward M. Perkins ◽  
Michael Marino ◽  
Jason A. Mears ◽  
J. Michael McCaffery ◽  
...  
Keyword(s):  
Self Assembly ◽  
Membrane Dynamics ◽  
Nucleotide Hydrolysis ◽  
Mitochondrial Division ◽  
Cellular Processes ◽  
Self Assembling ◽  
Related Proteins ◽  
Rate Limiting ◽  
Common Function

Dynamin-related proteins (DRPs) are large self-assembling GTPases whose common function is to regulate membrane dynamics in a variety of cellular processes. Dnm1, which is a yeast DRP (Drp1/Dlp1 in humans), is required for mitochondrial division, but its mechanism is unknown. We provide evidence that Dnm1 likely functions through self-assembly to drive the membrane constriction event that is associated with mitochondrial division. Two regulatory features of Dnm1 self-assembly were also identified. Dnm1 self-assembly proceeded through a rate-limiting nucleation step, and nucleotide hydrolysis by assembled Dnm1 structures was highly cooperative with respect to GTP. Dnm1 formed extended spirals, which possessed diameters greater than those of dynamin-1 spirals but whose sizes, remarkably, were equal to those of mitochondrial constriction sites in vivo. These data suggest that Dnm1 has evolved to form structures that fit the dimensions of mitochondria.

scholarly journals ACTN4 Mediates SEPT14 Mutation-Induced Sperm Head Defects

Biomedicines ◽  
2020 ◽  
Vol 8 (11) ◽  
pp. 518
Author(s):  
Yu-Hua Lin ◽  
Chia-Yen Huang ◽  
Chih-Chun Ke ◽  
Ya-Yun Wang ◽  
Tsung-Hsuan Lai ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Model ◽  
Membrane Dynamics ◽  
Sperm Head ◽  
Cellular Processes ◽  
Germ Cell Line ◽  
Head Formation ◽  
Fourth Component ◽  
Related Proteins ◽  
Cellular Components

Septins (SEPTs) are highly conserved GTP-binding proteins and the fourth component of the cytoskeleton. Polymerized SEPTs participate in the modulation of various cellular processes, such as cytokinesis, cell polarity, and membrane dynamics, through their interactions with microtubules, actin, and other cellular components. The main objective of this study was to dissect the molecular pathological mechanism of SEPT14 mutation-induced sperm head defects. To identify SEPT14 interactors, co-immunoprecipitation (co-IP) and nano-liquid chromatography-mass spectrometry/mass spectrometry were applied. Immunostaining showed that SEPT14 was significantly localized to the manchette structure. The SEPT14 interactors were identified and classified as (1) SEPT-, (2) microtubule-, (3) actin-, and (4) sperm structure-related proteins. One interactor, ACTN4, an actin-holding protein, was selected for further study. Co-IP experiments showed that SEPT14 interacts with ACTN4 in a male germ cell line. SEPT14 also co-localized with ACTN4 in the perinuclear and manchette regions of the sperm head in early elongating spermatids. In the cell model, mutated SEPT14 disturbed the localization pattern of ACTN4. In a clinical aspect, sperm with mutant SEPT14, SEPT14A123T (p.Ala123Thr), and SEPT14I333T (p.Ile333Thr), have mislocalized and fragmented ACTN4 signals. Sperm head defects in donors with SEPT14 mutations are caused by disruption of the functions of ACTN4 and actin during sperm head formation.

scholarly journals Lipid membranes trigger misfolding and self-assembly of amyloid β 42 protein into aggregates

2019 ◽  
Author(s):  
Siddhartha Banerjee ◽  
Mohtadin Hashemi ◽  
Karen Zagorski ◽  
Yuri L. Lyubchenko
Keyword(s):  
Self Assembly ◽  
Lipid Membranes ◽  
Membrane Surface ◽  
Amyloid Β ◽  
Test Tube ◽  
Aggregation Process ◽  
Self Assembling ◽  
Nanoscale Aggregates

AbstractThe assembly of polypeptides and proteins into nanoscale aggregates is a phenomenon observed in a vast majority of proteins. Importantly, aggregation of amyloid β (Aβ) proteins is considered as a major cause for the development of Alzheimer’s disease. The process depends on various conditions and typical test-tube experiments require high protein concentration that complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here we demonstrate that Aβ42 monomers at the membrane bilayer are capable of self-assembling into aggregates at physiologically low concentrations, and the membrane in this aggregation process plays a role of a catalyst. We applied all-atom molecular dynamics to demonstrate that the interaction with the membrane surface dramatically changes the conformation of Aβ42 protein. As a result, the misfolded Aβ42 rapidly assembles into dimers, trimers and tetramers, so the on-surface aggregation is the mechanism by which amyloid oligomers are produced and spread.

scholarly journals Mitochondrial division, fusion and degradation

2019 ◽  
Vol 167 (3) ◽  
pp. 233-241 ◽  
Author(s):  
Daisuke Murata ◽  
Kenta Arai ◽  
Miho Iijima ◽  
Hiromi Sesaki
Keyword(s):  
Super Resolution ◽  
Healthy Population ◽  
Lipid Biochemistry ◽  
Mitochondrial Division ◽  
Cellular Processes ◽  
Size Number ◽  
Wide Range ◽  
Autophagic Degradation ◽  
And Function

Abstract The mitochondrion is an essential organelle for a wide range of cellular processes, including energy production, metabolism, signal transduction and cell death. To execute these functions, mitochondria regulate their size, number, morphology and distribution in cells via mitochondrial division and fusion. In addition, mitochondrial division and fusion control the autophagic degradation of dysfunctional mitochondria to maintain a healthy population. Defects in these dynamic membrane processes are linked to many human diseases that include metabolic syndrome, myopathy and neurodegenerative disorders. In the last several years, our fundamental understanding of mitochondrial fusion, division and degradation has been significantly advanced by high resolution structural analyses, protein-lipid biochemistry, super resolution microscopy and in vivo analyses using animal models. Here, we summarize and discuss this exciting recent progress in the mechanism and function of mitochondrial division and fusion.

scholarly journals Self-assembly of an anion receptor with metal-dependent kinase inhibition and potent in vitro anti-cancer properties

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Simon J. Allison ◽  
Jaroslaw Bryk ◽  
Christopher J. Clemett ◽  
Robert A. Faulkner ◽  
Michael Ginger ◽  
...  
Keyword(s):  
Self Assembly ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Selective Inhibition ◽  
Human Cancer Cell Lines ◽  
Cellular Processes ◽  
Self Assembling ◽  
Anti Cancer ◽  
Anionic Species

AbstractOne topical area of supramolecular chemistry is the binding of anionic species but despite the importance of anions in diverse cellular processes and for cancer development, anion receptors or ‘binders’ have received little attention as potential anti-cancer therapeutics. Here we report self-assembling trimetallic cryptands (e.g. [L2(Metal)3]6+ where Metal = Cu2+, Zn2+ or Mn2+) which can encapsulate a range of anions and which show metal-dependent differences in chemical and biological reactivities. In cell studies, both [L2Cu3]6+ and [L2Zn3]6+ complexes are highly toxic to a range of human cancer cell lines and they show significant metal-dependent selective activity towards cancer cells compared to healthy, non-cancerous cells (by up to 2000-fold). The addition of different anions to the complexes (e.g. PO43ˉ, SO42ˉ or PhOPO32ˉ) further alters activity and selectivity allowing the activity to be modulated via a self-assembly process. The activity is attributed to the ability to either bind or hydrolyse phosphate esters and mechanistic studies show differential and selective inhibition of multiple kinases by both [L2Cu3]6+ and [L2Zn3]6+ complexes but via different mechanisms.

Molecular self-assembly of a tyroservatide-derived octapeptide and hydroxycamptothecin for enhanced therapeutic efficacy

Nanoscale ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 5094-5102
Author(s):  
Jing Liu ◽  
Can Wu ◽  
Guoru Dai ◽  
Feng Feng ◽  
Yuquan Chi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Self Assembly ◽  
Therapeutic Efficacy ◽  
Self Assembling

A pure l-amino acid-based molecular hydrogel was designed through conjugation of an anticancer tripeptide tyroservatide (YSV) with a self-assembling moiety, which enhanced therapeutic efficacy of both YSV and hydroxycamptothecin in vitro and in vivo.

The general concept of molecular chaperones

1993 ◽  
Vol 339 (1289) ◽  
pp. 257-261 ◽  
Keyword(s):  
Heat Shock ◽  
Molecular Chaperones ◽  
Self Assembly ◽  
General Concept ◽  
Biological Functions ◽  
Protein Surfaces ◽  
Cellular Processes ◽  
Introductory Article ◽  
Protein Molecules

This introductory article proposes a conceptual framework in which to consider the information that is emerging about the proteins called molecular chaperones, and suggests some definitions that may be useful in this new field of biochemistry. Molecular chaperones are currently defined in functional terms as a class of unrelated families of protein that assist the correct non-covalent assembly of other polypeptide-containing structures in vivo , but which are not components of these assembled structures when they are performing their normal biological functions. The term assembly in this definition embraces not only the folding of newly synthesized polypeptides and any association into oligomers that may occur, but also includes any changes in the degree of either folding or association that may take place when proteins carry out their functions, are transported across membranes, or are repaired or destroyed after stresses such as heat shock. Known molecular chaperones do not convey steric information essential for correct assembly, but appear to act by binding to interactive protein surfaces that are transiently exposed during various cellular processes; this binding inhibits incorrect interactions that may otherwise produce non-functional structures. Thus the concept of molecular chaperones does not contradict the principle of protein self-assembly, but qualifies it by suggesting that in vivo self-assembly requires assistance by other protein molecules.

scholarly journals Peptide Nanomaterials for Drug Delivery Applications

2020 ◽  
Vol 21 (4) ◽  
pp. 401-412 ◽  
Author(s):  
Sreekanth Pentlavalli ◽  
Sophie Coulter ◽  
Garry Laverty
Keyword(s):  
Drug Delivery ◽  
Self Assembly ◽  
Diverse Range ◽  
Drug Molecules ◽  
Sustained Drug Delivery ◽  
Self Assembling ◽  
Wide Range ◽  
Methods Of Synthesis ◽  
Self Assembled

Self-assembled peptides have been shown to form well-defined nanostructures which display outstanding characteristics for many biomedical applications and especially in controlled drug delivery. Such biomaterials are becoming increasingly popular due to routine, standardized methods of synthesis, high biocompatibility, biodegradability and ease of upscale. Moreover, one can modify the structure at the molecular level to form various nanostructures with a wide range of applications in the field of medicine. Through environmental modifications such as changes in pH and ionic strength and the introduction of enzymes or light, it is possible to trigger self-assembly and design a host of different self-assembled nanostructures. The resulting nanostructures include nanotubes, nanofibers, hydrogels and nanovesicles which all display a diverse range of physico-chemical and mechanical properties. Depending on their design, peptide self-assembling nanostructures can be manufactured with improved biocompatibility and in vivo stability and the ability to encapsulate drugs with the capacity for sustained drug delivery. These molecules can act as carriers for drug molecules to ferry cargo intracellularly and respond to stimuli changes for both hydrophilic and hydrophobic drugs. This review explores the types of self-assembling nanostructures, the effects of external stimuli on and the mechanisms behind the assembly process, and applications for such technology in drug delivery.

Self-assembling RATEA16 peptide nanofiber designed for rapid hemostasis

2020 ◽  
Vol 8 (9) ◽  
pp. 1897-1905 ◽  
Author(s):  
Shuda Wei ◽  
Fangping Chen ◽  
Zhen Geng ◽  
Ruihua Cui ◽  
Yujiao Zhao ◽  
...  
Keyword(s):  
Secondary Structure ◽  
Self Assembly ◽  
Solid Phase ◽  
Phase Method ◽  
Self Assembling ◽  
Solid Phase Method ◽  
Assembly Performance

In this study, we synthesized a novel polypeptide material, RATEA16, by the solid phase method, and investigated the secondary structure, self-assembly performance, gelation ability, biocompatibility and hemostatic efficiency in vitro and in vivo.

scholarly journals Self-Assembly of Tail Tube Protein of Bacteriophage vB_EcoS_NBD2 into Extremely Long Polytubes in E. coli and S. cerevisiae

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 208 ◽  
Author(s):  
Aliona Špakova ◽  
Eugenijus Šimoliūnas ◽  
Raminta Batiuškaitė ◽  
Simonas Pajeda ◽  
Rolandas Meškys ◽  
...  
Keyword(s):  
Self Assembly ◽  
Tail Length ◽  
Cell Protein ◽  
Tubular Structures ◽  
E Coli ◽  
Physical Conditions ◽  
Self Assembling ◽  
Phage Proteins ◽  
Purification Protocol

Nucleotides, peptides and proteins serve as a scaffold material for self-assembling nanostructures. In this study, the production of siphovirus vB_EcoS_NBD2 (NBD2) recombinant tail tube protein gp39 reached approximately 33% and 27% of the total cell protein level in Escherichia coli and Saccharomyces cerevisiae expression systems, respectively. A simple purification protocol allowed us to produce a recombinant gp39 protein with 85%–90% purity. The yield of gp39 was 2.9 ± 0.36 mg/g of wet E. coli cells and 0.85 ± 0.33 mg/g for S. cerevisiae cells. The recombinant gp39 self-assembled into well-ordered tubular structures (polytubes) in vivo in the absence of other phage proteins. The diameter of these structures was the same as the diameter of the tail of phage NBD2 (~12 nm). The length of these structures varied from 0.1 µm to >3.95 µm, which is 23-fold the normal NBD2 tail length. Stability analysis demonstrated that the polytubes could withstand various chemical and physical conditions. These polytubes show the potential to be used as a nanomaterial in various fields of science.

scholarly journals An S/T motif controls reversible oligomerization of the Hsp40 chaperone DNAJB6b through subtle reorganization of a β sheet backbone

2020 ◽  
Vol 117 (48) ◽  
pp. 30441-30450
Author(s):  
Theodoros K. Karamanos ◽  
Vitali Tugarinov ◽  
G. Marius Clore
Keyword(s):  
Self Assembly ◽  
Nmr Relaxation ◽  
Relaxation Dispersion ◽  
Nmr Studies ◽  
Self Assembling ◽  
Critical Residues ◽  
Nmr Methods ◽  
Β Sheet

Chaperone oligomerization is often a key aspect of their function. Irrespective of whether chaperone oligomers act as reservoirs for active monomers or exhibit a chaperoning function themselves, understanding the mechanism of oligomerization will further our understanding of how chaperones maintain the proteome. Here, we focus on the class-II Hsp40, human DNAJB6b, a highly efficient inhibitor of protein self-assembly in vivo and in vitro that forms functional oligomers. Using single-quantum methyl-based relaxation dispersion NMR methods we identify critical residues for DNAJB6b oligomerization in its C-terminal domain (CTD). Detailed solution NMR studies on the structure of the CTD showed that a serine/threonine-rich stretch causes a backbone twist in the N-terminal β strand, stabilizing the monomeric form. Quantitative analysis of an array of NMR relaxation-based experiments (including Carr–Purcell–Meiboom–Gill relaxation dispersion, off-resonanceR1ρprofiles, lifetime line broadening, and exchange-induced shifts) on the CTD of both wild type and a point mutant (T142A) within the S/T region of the first β strand delineates the kinetics of the interconversion between the major twisted-monomeric conformation and a more regular β strand configuration in an excited-state dimer, as well as exchange of both monomer and dimer species with high-molecular-weight oligomers. These data provide insights into the molecular origins of DNAJB6b oligomerization. Further, the results reported here have implications for the design of β sheet proteins with tunable self-assembling properties and pave the way to an atomic-level understanding of amyloid inhibition.

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