Regulation of myosin 5a and myosin 7a

2011 ◽  
Vol 39 (5) ◽  
pp. 1136-1141 ◽  
Author(s):  
Verl B. Siththanandan ◽  
James R. Sellers
Keyword(s):  
Cellular Function ◽  
Enzymatic Activities ◽  
Motor Domain ◽  
Present Review ◽  
Structural Basis ◽  
Ion Binding ◽  
Inactive State ◽  
Kinetic Mechanisms ◽  
Myosin Superfamily

The myosin superfamily is diverse in its structure, kinetic mechanisms and cellular function. The enzymatic activities of most myosins are regulated by some means such as Ca2+ ion binding, phosphorylation or binding of other proteins. In the present review, we discuss the structural basis for the regulation of mammalian myosin 5a and Drosophila myosin 7a. We show that, although both myosins have a folded inactive state in which domains in the myosin tail interact with the motor domain, the details of the regulation of these two myosins differ greatly.

scholarly journals Laboratory Diagnosis of Porphyria

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1343
Author(s):  
Elena Di Pierro ◽  
Michele De Canio ◽  
Rosa Mercadante ◽  
Maria Savino ◽  
Francesca Granata ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Diagnostic Testing ◽  
Laboratory Diagnosis ◽  
Clinical Suspicion ◽  
Enzymatic Activities ◽  
Heme Biosynthesis ◽  
Present Review ◽  
Biosynthesis Pathway ◽  
Clinical Presentations

Porphyrias are a group of diseases that are clinically and genetically heterogeneous and originate mostly from inherited dysfunctions of specific enzymes involved in heme biosynthesis. Such dysfunctions result in the excessive production and excretion of the intermediates of the heme biosynthesis pathway in the blood, urine, or feces, and these intermediates are responsible for specific clinical presentations. Porphyrias continue to be underdiagnosed, although laboratory diagnosis based on the measurement of metabolites could be utilized to support clinical suspicion in all symptomatic patients. Moreover, the measurement of enzymatic activities along with a molecular analysis may confirm the diagnosis and are, therefore, crucial for identifying pre-symptomatic carriers. The present review provides an overview of the laboratory assays used most commonly for establishing the diagnosis of porphyria. This would assist the clinicians in prescribing appropriate diagnostic testing and interpreting the testing results.

scholarly journals Structural basis of ion transport and inhibition in ferroportin

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yaping Pan ◽  
Zhenning Ren ◽  
Shuai Gao ◽  
Jiemin Shen ◽  
Lie Wang ◽  
...  
Keyword(s):  
Binding Sites ◽  
Metal Ion ◽  
Peptide Hormone ◽  
Structural Basis ◽  
Deficiency Anemia ◽  
Pharmacological Intervention ◽  
Ion Binding ◽  
Coupled Transport ◽  
Metal Ion Binding ◽  
Ion Binding Sites

Abstract Ferroportin is an iron exporter essential for releasing cellular iron into circulation. Ferroportin is inhibited by a peptide hormone, hepcidin. In humans, mutations in ferroportin lead to ferroportin diseases that are often associated with accumulation of iron in macrophages and symptoms of iron deficiency anemia. Here we present the structures of the ferroportin from the primate Philippine tarsier (TsFpn) in the presence and absence of hepcidin solved by cryo-electron microscopy. TsFpn is composed of two domains resembling a clamshell and the structure defines two metal ion binding sites, one in each domain. Both structures are in an outward-facing conformation, and hepcidin binds between the two domains and reaches one of the ion binding sites. Functional studies show that TsFpn is an electroneutral H+/Fe2+ antiporter so that transport of each Fe2+ is coupled to transport of two H+ in the opposite direction. Perturbing either of the ion binding sites compromises the coupled transport of H+ and Fe2+. These results establish the structural basis of metal ion binding, transport and inhibition in ferroportin and provide a blueprint for targeting ferroportin in pharmacological intervention of ferroportin diseases.

scholarly journals Cytokinesis Depends on the Motor Domains of Myosin-II in Fission Yeast but Not in Budding Yeast

2005 ◽  
Vol 16 (11) ◽  
pp. 5346-5355 ◽  
Author(s):  
Matthew Lord ◽  
Ellen Laves ◽  
Thomas D. Pollard
Keyword(s):  
Atpase Activity ◽  
Fission Yeast ◽  
Mechanism Of Action ◽  
Budding Yeast ◽  
Myosin Ii ◽  
Cellular Function ◽  
Motor Domain ◽  
Actin Binding ◽  
Contractile Ring ◽  
Head Domain

Budding yeast possesses one myosin-II, Myo1p, whereas fission yeast has two, Myo2p and Myp2p, all of which contribute to cytokinesis. We find that chimeras consisting of Myo2p or Myp2p motor domains fused to the tail of Myo1p are fully functional in supporting budding yeast cytokinesis. Remarkably, the tail alone of budding yeast Myo1p localizes to the contractile ring, supporting both its constriction and cytokinesis. In contrast, fission yeast Myo2p and Myp2p require both the catalytic head domain as well as tail domains for function, with the tails providing distinct functions ( Bezanilla and Pollard, 2000 ). Myo1p is the first example of a myosin whose cellular function does not require a catalytic motor domain revealing a novel mechanism of action for budding yeast myosin-II independent of actin binding and ATPase activity.

Structural basis for DNA-mediated allosteric regulation facilitated by the AAA+module of Lon protease

2014 ◽  
Vol 70 (2) ◽  
pp. 218-230 ◽  
Author(s):  
Alan Yueh-Luen Lee ◽  
Yu-Da Chen ◽  
Yu-Yung Chang ◽  
Yu-Ching Lin ◽  
Chi-Fon Chang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Dna Binding ◽  
Electrostatic Interactions ◽  
Allosteric Regulation ◽  
Binding Mode ◽  
Negative Regulation ◽  
Enzymatic Activities ◽  
Structural Basis ◽  
Lon Protease ◽  
Arginine Residues

Lon belongs to a unique group of AAA+proteases that bind DNA. However, the DNA-mediated regulation of Lon remains elusive. Here, the crystal structure of the α subdomain of the Lon protease fromBrevibacillus thermoruber(Bt-Lon) is presented, together with biochemical data, and the DNA-binding mode is delineated, showing that Arg518, Arg557 and Arg566 play a crucial role in DNA binding. Electrostatic interactions contributed by arginine residues in the AAA+module are suggested to be important to DNA binding and allosteric regulation of enzymatic activities. Intriguingly, Arg557, which directly binds DNA in the α subdomain, has a dual role in the negative regulation of ATPase stimulation by DNA and in the domain–domain communication in allosteric regulation of Bt-Lon by substrate. In conclusion, structural and biochemical evidence is provided to show that electrostatic interaction in the AAA+module is important for DNA binding by Lon and allosteric regulation of its enzymatic activities by DNA and substrate.

scholarly journals Structural basis for C-type inactivation in a Shaker family voltage gated K+ channel

2021 ◽  
Author(s):  
Ravikumar Reddi ◽  
Kimberly Matulef ◽  
Erika A. Riederer ◽  
Matthew R. Whorton ◽  
Francis I. Valiyaveetil
Keyword(s):  
Crystal Structure ◽  
Binding Sites ◽  
Structural Changes ◽  
Selectivity Filter ◽  
Structural Basis ◽  
K Channel ◽  
Ion Binding ◽  
Channel Pore ◽  
Voltage Gated ◽  
Ion Binding Sites

AbstractC-type inactivation is a process by which ion flux through a voltage-gated K+ (Kv) channel is regulated at the selectivity filter. While prior studies have indicated that C-type inactivation involves structural changes at the selectivity filter, the nature of the changes have not been resolved. Here we report the crystal structure of the Kv1.2 channel in a C-type inactivated state. The structure shows that C-type inactivation involves changes in the selectivity filter that disrupt the outer two ion binding sites in the filter. The changes at the selectivity filter propagate to the extracellular mouth and the turret regions of the channel pore. The structural changes observed are consistent with the functional hallmarks of C-type inactivation. This study highlights the intricate interplay between K+ occupancy at the ion binding sites and the interactions of the selectivity filter in determining the balance between the conductive and the inactivated conformations of the filter.

scholarly journals Cryo-EM structures reveal specialization at the myosin VI-actin interface and a mechanism of force sensitivity

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Pinar S Gurel ◽  
Laura Y Kim ◽  
Paul V Ruijgrok ◽  
Tosan Omabegho ◽  
Zev Bryant ◽  
...  
Keyword(s):  
Bound States ◽  
Motor Domain ◽  
Myosin Vi ◽  
Primary Sequence ◽  
Evolutionary Path ◽  
Force Sensitivity ◽  
Mechanochemical Cycle ◽  
Structural Diversification ◽  
Insight Into ◽  
Myosin Superfamily

Despite extensive scrutiny of the myosin superfamily, the lack of high-resolution structures of actin-bound states has prevented a complete description of its mechanochemical cycle and limited insight into how sequence and structural diversification of the motor domain gives rise to specialized functional properties. Here we present cryo-EM structures of the unique minus-end directed myosin VI motor domain in rigor (4.6 Å) and Mg-ADP (5.5 Å) states bound to F-actin. Comparison to the myosin IIC-F-actin rigor complex reveals an almost complete lack of conservation of residues at the actin-myosin interface despite preservation of the primary sequence regions composing it, suggesting an evolutionary path for motor specialization. Additionally, analysis of the transition from ADP to rigor provides a structural rationale for force sensitivity in this step of the mechanochemical cycle. Finally, we observe reciprocal rearrangements in actin and myosin accompanying the transition between these states, supporting a role for actin structural plasticity during force generation by myosin VI.

scholarly journals Gating mechanism of cardiac ryanodine receptor 2 upon calcium ion binding

2020 ◽  
Author(s):  
Takuya Kobayashi ◽  
Akihisa Tsutsumi ◽  
Nagomi Kurebayashi ◽  
Kei Saito ◽  
Masami Kodama ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Heart Diseases ◽  
Atomic Level ◽  
Structural Basis ◽  
Ion Binding ◽  
Release Channel ◽  
Cryo Electron Microscopy ◽  
Gating Mechanism ◽  
Channel Opening ◽  
Cardiac Ryanodine Receptor

AbstractCardiac ryanodine receptor (RyR2) is a large Ca2+ release channel in the sarcoplasmic reticulum and indispensable for excitation-contraction coupling in the heart. RyR2 is activated by Ca2+ and RyR2 mutations have been implicated in severe arrhythmogenic heart diseases. Yet, the structural basis underlying channel opening and how mutations affect the channel remain unknown. Here, we combined high-resolution structures determined by cryo-electron microscopy with quantitative functional analysis of channels carrying various mutations in specific residues. We demonstrated that interactions close to the channel pore are important for stabilizing the channel in the closed state and those in the surrounding regions are essential for channel opening. Our results reveal mechanisms underlying channel opening upon Ca2+ binding and alterations by pathogenic mutations of RyR2 at the atomic level.One Sentence SummaryKey movements and interactions in RyR2 during cardiac Ca2+ channel opening are clarified at the atomic level.

scholarly journals Structural Basis for Cytoplasmic Dynein-1 Regulation by Lis1

2021 ◽  
Author(s):  
John P Gillies ◽  
Janice M Reimer ◽  
Eva P Karasmanis ◽  
Indrajit Lahiri ◽  
Zaw Min Htet ◽  
...  
Keyword(s):  
High Resolution ◽  
Cytoplasmic Dynein ◽  
Motor Domain ◽  
Structural Basis ◽  
Neurodevelopmental Disease ◽  
Microtubule Motor ◽  
High Resolution Structure ◽  
Resolution Structure

The lissencephaly 1 gene, LIS1, is mutated in patients with the neurodevelopmental disease lissencephaly. The Lis1 protein is conserved from fungi to mammals and is a key regulator of cytoplasmic dynein-1, the major minus-end-directed microtubule motor in many eukaryotes. Lis1 is the only dynein regulator that binds directly to dynein's motor domain, and by doing so alters dynein's mechanochemistry. Lis1 is required for the formation of fully active dynein complexes, which also contain essential cofactors: dynactin and an activating adaptor. Here, we report the first high-resolution structure of the yeast dynein-Lis1 complex. Our 3.1Å structure reveals, in molecular detail, the major contacts between dynein and Lis1 and between Lis1's β-propellers. Structure-guided mutations in Lis1 and dynein show that these contacts are required for Lis1's ability to form fully active human dynein complexes and to regulate yeast dynein's mechanochemistry and in vivo function. We present a model for the conserved role of Lis1 in regulating dynein from yeast to humans.

scholarly journals Structural basis for cytoplasmic dynein-1 regulation by Lis1

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
John P Gillies ◽  
Janice M Reimer ◽  
Eva P Karasmanis ◽  
Indrajit Lahiri ◽  
Zaw Min Htet ◽  
...  
Keyword(s):  
High Resolution ◽  
Cytoplasmic Dynein ◽  
Motor Domain ◽  
Structural Basis ◽  
Neurodevelopmental Disease ◽  
Molecular Detail ◽  
Microtubule Motor ◽  
High Resolution Structure ◽  
Resolution Structure

The lissencephaly 1 gene, LIS1, is mutated in patients with the neurodevelopmental disease lissencephaly. The Lis1 protein is conserved from fungi to mammals and is a key regulator of cytoplasmic dynein-1, the major minus-end-directed microtubule motor in many eukaryotes. Lis1 is the only dynein regulator known to bind directly to dynein's motor domain, and by doing so alters dynein's mechanochemistry. Lis1 is required for the formation of fully active dynein complexes, which also contain essential cofactors: dynactin and an activating adaptor. Here, we report the first high-resolution structure of the yeast dynein–Lis1 complex. Our 3.1Å structure reveals, in molecular detail, the major contacts between dynein and Lis1 and between Lis1's ß-propellers. Structure-guided mutations in Lis1 and dynein show that these contacts are required for Lis1's ability to form fully active human dynein complexes and to regulate yeast dynein's mechanochemistry and in vivo function.

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