scholarly journals A highly conserved 310 helix within the kinesin motor domain is critical for kinesin function and human health

2021 ◽  
Vol 7 (18) ◽  
pp. eabf1002
Author(s):  
Aileen J. Lam ◽  
Lu Rao ◽  
Yuzu Anazawa ◽  
Kyoko Okada ◽  
Kyoko Chiba ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Fundamental Principle ◽  
Association Rate ◽  
Biophysical Parameters ◽  
Kinesin Motor ◽  
Cargo Transport ◽  
The Family ◽  
Loop Conformation ◽  
Conserved Residue ◽  
310 Helix

KIF1A is a critical cargo transport motor within neurons. More than 100 known mutations result in KIF1A-associated neurological disorder (KAND), a degenerative condition for which there is no cure. A missense mutation, P305L, was identified in children diagnosed with KAND, but the molecular basis for the disease is unknown. We find that this conserved residue is part of an unusual 310 helix immediately adjacent to the family-specific K-loop, which facilitates a high microtubule-association rate. We find that the mutation negatively affects several biophysical parameters of the motor. However, the microtubule-association rate of the motor is most markedly affected, revealing that the presence of an intact K-loop is not sufficient for its function. We hypothesize that the 310 helix facilitates a specific K-loop conformation that is critical for its function. We find that the function of this proline is conserved in kinesin-1, revealing a fundamental principle of the kinesin motor mechanism.

scholarly journals A Highly Conserved 310-Helix Within the Kinesin Motor Domain is Critical for Kinesin Function and Human Health

2020 ◽  
Author(s):  
Aileen J. Lam ◽  
Lu Rao ◽  
Yuzu Anazawa ◽  
Kyoko Okada ◽  
Kyoko Chiba ◽  
...  
Keyword(s):  
Single Molecule ◽  
De Novo ◽  
Fundamental Principle ◽  
Association Rate ◽  
Long Distance ◽  
Kinesin Motor ◽  
Molecular Defects ◽  
Neurological Conditions ◽  
Loop Conformation ◽  
Kinesin Family

AbstractKIF1A, a kinesin-3 family member, plays critical roles as a long-distance cargo-transporter within neurons. Over 100 known KIF1A mutations in humans result in KIF1A Associated Neurological Disease (KAND), developmental and degenerative neurological conditions for which there is no cure. A de novo missense mutation, P305L, was recently identified in several children diagnosed with KAND, but the underlying molecular basis for the disease phenotype is unknown. Interestingly, this residue is highly conserved in kinesin-family proteins, and together with adjacent conserved residues also implicated in KAND, forms an unusual 310-helical element immediately C-terminal to loop-12 (L12, also known as the K-loop in KIF1A) in the conserved kinesin motor core. In KIF1A, the disordered K-loop contains a highly charged insertion of lysines that is thought to endow the motor with a high microtubule-association rate. Here, we characterize the molecular defects of the P305L mutation in KIF1A using genetic, biochemical, and single-molecule approaches. We find the mutation negatively impacts the velocity, run-length, and force generation of the motor. However, a much more dramatic effect is observed on the microtubule-association rate of the motor, revealing that the presence of an intact K-loop is not sufficient for its function. We hypothesize that an elusive K-loop conformation, mediated by formation of a highly conserved adjacent 310-helix that is modulated via P305, is critically important for the kinesin-microtubule interaction. Importantly, we find that the function of this proline is conserved in the canonical kinesin, KIF5, revealing a fundamental principle of the kinesin motor mechanism.

scholarly journals The family-specific K-loop influences the microtubule on-rate but not the superprocessivity of kinesin-3 motors

2014 ◽  
Vol 25 (14) ◽  
pp. 2161-2170 ◽  
Author(s):  
Virupakshi Soppina ◽  
Kristen J. Verhey
Keyword(s):  
Bound State ◽  
Motor Domain ◽  
Cellular Transport ◽  
Kinesin Motor ◽  
Cargo Transport ◽  
The Family ◽  
Initial Interaction ◽  
Kinesin Superfamily ◽  
Positively Charged ◽  
Functional Output

The kinesin-3 family (KIF) is one of the largest among the kinesin superfamily and an important driver of a variety of cellular transport events. Whereas all kinesins contain the highly conserved kinesin motor domain, different families have evolved unique motor features that enable different mechanical and functional outputs. A defining feature of kinesin-3 motors is the presence of a positively charged insert, the K-loop, in loop 12 of their motor domains. However, the mechanical and functional output of the K-loop with respect to processive motility of dimeric kinesin-3 motors is unknown. We find that, surprisingly, the K-loop plays no role in generating the superprocessive motion of dimeric kinesin-3 motors (KIF1, KIF13, and KIF16). Instead, we find that the K-loop provides kinesin-3 motors with a high microtubule affinity in the motor's ADP-bound state, a state that for other kinesins binds only weakly to the microtubule surface. A high microtubule affinity results in a high landing rate of processive kinesin-3 motors on the microtubule surface. We propose that the family-specific K-loop contributes to efficient kinesin-3 cargo transport by enhancing the initial interaction of dimeric motors with the microtubule track.

scholarly journals Exotoxins of Staphylococcus aureus

2000 ◽  
Vol 13 (1) ◽  
pp. 16-34 ◽  
Author(s):  
Martin M. Dinges ◽  
Paul M. Orwin ◽  
Patrick M. Schlievert
Keyword(s):  
Staphylococcus Aureus ◽  
Toxic Shock Syndrome ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Food Poisoning ◽  
Structure And Function ◽  
Toxic Shock ◽  
The Family ◽  
Toxic Shock Syndrome Toxin ◽  
And Function

SUMMARY This article reviews the literature regarding the structure and function of two types of exotoxins expressed by Staphylococcus aureus, pyrogenic toxin superantigens (PTSAgs) and hemolysins. The molecular basis of PTSAg toxicity is presented in the context of two diseases known to be caused by these exotoxins: toxic shock syndrome and staphylococcal food poisoning. The family of staphylococcal PTSAgs presently includes toxic shock syndrome toxin-1 (TSST-1) and most of the staphylococcal enterotoxins (SEs) (SEA, SEB, SEC, SED, SEE, SEG, and SEH). As the name implies, the PTSAgs are multifunctional proteins that invariably exhibit lethal activity, pyrogenicity, superantigenicity, and the capacity to induce lethal hypersensitivity to endotoxin. Other properties exhibited by one or more staphylococcal PTSAgs include emetic activity (SEs) and penetration across mucosal barriers (TSST-1). A detailed review of the molecular mechanisms underlying the toxicity of the staphylococcal hemolysins is also presented.

All in the Family: Primary Megakaryocytes for Studies of Platelet αIIbβ3 Signaling

2001 ◽  
Vol 86 (07) ◽  
pp. 259-265 ◽  
Author(s):  
Andrew Leavitt ◽  
Sanford Shattil
Keyword(s):  
Molecular Basis ◽  
Intrinsic Value ◽  
Model System ◽  
Integrin Signaling ◽  
Gene Products ◽  
Hematopoietic Stem ◽  
The Family ◽  
Viral Transduction ◽  
Inside Out ◽  
Platelet Formation

SummaryIntegrin αIIbβ3 mediates key platelet adhesive responses during hemostasis and thrombosis. Adhesive ligand binding to αIIbβ3 is regulated by “inside-out” signals, while adhesion-dependent cytoskeletal events are regulated by “outside-in” signals from αIIbβ3. Currently, the molecular basis of bidirectional αIIbβ3 signaling is incompletely understood. The functional assessment of integrin signaling pathways in nucleated cells has been facilitated by techniques such as viral transduction which enable expression of dominant-active and dominant-inhibitory gene products. This approach cannot be used with anucleate platelets. However, recent advances in the ability to expand human and murine megakaryocytes from hematopoietic stem cells provide a tractable and genetically manipulatable system for studies of αIIbβ3 signaling. This overview will discuss some of the advantages and limitations of this approach and provide examples of its utility. Thus, in addition to their intrinsic value for understanding hematopoiesis and platelet formation, primary megakaryocytes represent a model system complementary to platelets for unraveling the remaining mysteries of αIIbβ3 signaling.

scholarly journals Anticipation in an Indo-Canadian Family with Crohn's Disease

2001 ◽  
Vol 15 (10) ◽  
pp. 695-698 ◽  
Author(s):  
Hugh J Freeman ◽  
Noel B Hershfield
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Neurological Disorders ◽  
Molecular Basis ◽  
Present Report ◽  
Phenotypic Expression ◽  
Apparent Increase ◽  
The Family ◽  
Perianal Sepsis ◽  
Common Environmental Factor

Genetic anticipation, associated elsewhere with monogenic neurological disorders, has been hypothesized to be present in familial forms of Crohn's disease. Usually, with studies of parent-child pairs, the parent who is initially diagnosed is older at the onset of disease than the child. With each successive generation, an apparent increase in disease severity or behaviour occurs. This phenomenon is believed to have a molecular basis. In the present report, an Indo-Canadian family with Crohn's disease is described. In all members of the family, disease was diagnosed only after prolonged residence in Canada, supporting the view that Crohn's disease arises in individuals with a genetic predisposition following exposure to some, as yet unknown, common environmental factor. Three siblings with Crohn's disease, first diagnosed between ages 15 and 27 years, or six to 11 years after arrival in Canada, had phenotypically concordant disease localized in the ileum and colon, with fistulizing complications, including perianal sepsis. Crohn's disease was only diagnosed in the father at the age of 76 years, almost three decades after his arrival in Canada. His disease was localized to the ileum and had a fibrostenosing behaviour. This is the first reported instance of familial Crohn's disease in an immigrant population, illustrating potential biases in genetically based studies of Crohn's disease that rely solely on phenotypic expression.

scholarly journals Molecular basis for the preferential recognition of β1,3‐1,4‐glucans by the family 11 carbohydrate‐binding module from Clostridium thermocellum

FEBS Journal ◽  
2019 ◽  
Vol 287 (13) ◽  
pp. 2723-2743 ◽  
Author(s):  
Diana O. Ribeiro ◽  
Aldino Viegas ◽  
Virgínia M. R. Pires ◽  
João Medeiros‐Silva ◽  
Pedro Bule ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Clostridium Thermocellum ◽  
Carbohydrate Binding ◽  
Carbohydrate Binding Module ◽  
The Family ◽  
Preferential Recognition

scholarly journals F-actin disassembly factor MICAL1 binding to Myosin Va mediates cargo unloading during cytokinesis

2020 ◽  
Vol 6 (45) ◽  
pp. eabb1307 ◽  
Author(s):  
Fengfeng Niu ◽  
Kang Sun ◽  
Wenjie Wei ◽  
Cong Yu ◽  
Zhiyi Wei
Keyword(s):  
Intracellular Trafficking ◽  
Molecular Basis ◽  
Complex Structure ◽  
Actin Dynamics ◽  
Actin Assembly ◽  
Binding Partner ◽  
Cargo Transport ◽  
Binding Surface ◽  
Myosin Va

Motor-mediated intracellular trafficking requires motors to position cargoes at proper locations. Myosin Va (MyoVa), an actin-based motor, is a classic model for studying cargo transport. However, the molecular basis underlying cargo unloading in MyoVa-mediated transport has remained enigmatic. We have identified MICAL1, an F-actin disassembly regulator, as a binding partner of MyoVa and shown that MICAL1-MyoVa interaction is critical for localization of MyoVa at the midbody. By binding to MICAL1, MyoVa-mediated transport is terminated, resulting in vesicle unloading at the midbody for efficient cytokinesis. The MyoVa/MICAL1 complex structure reveals that MICAL1 and F-actin assembly factors, Spires, share an overlapped binding surface on MyoVa, suggesting a regulatory role of F-actin dynamics in cargo unloading. Down-regulating F-actin disassembly by a MICAL1 mutant significantly reduces MyoVa and vesicles accumulating at the midbody. Collectively, our findings demonstrate that MyoVa binds to MICAL1 at the midbody destination and triggers F-actin disassembly to unload the vesicle cargo.

Multigenerational Transition in Family Businesses: A New Explanatory Model

2005 ◽  
Vol 18 (4) ◽  
pp. 267-282 ◽  
Author(s):  
Johan Lambrecht
Keyword(s):  
Family Member ◽  
Transfer Process ◽  
Continuous Process ◽  
Fundamental Principle ◽  
Family Businesses ◽  
Explanatory Model ◽  
The Family ◽  
Individual Family ◽  
The Individual ◽  
Business Family

This article presents an explanatory model for transfer of family businesses to following generations. Our research using 10 case studies shows that transfer of family businesses is a lifelong, continuous process, in which the family must address and foster the soft elements of the transfer process: enterpreneurship, freedom, values, outside experience, upbringing, and education. Furthermore, a business family can develop into a family dynasty only when it embraces sound governance as a fundamental principle; that is, the individual family member belongs to the family, which belongs to the business.

scholarly journals Evaluation of MENA refugees’ attitudes towards patient autonomy-based ethics of informed consent

2021 ◽  
Author(s):  
Sukran Sevimli
Keyword(s):  
Informed Consent ◽  
Cultural Values ◽  
Developed Countries ◽  
Fundamental Principle ◽  
Quantitative Methodology ◽  
Mena Countries ◽  
Gender Differentials ◽  
Significant Difference ◽  
The Family ◽  
Male Authority

Abstract Background The objective of this study was to identify refugees’ attitudes concerning the autonomy-based ethics of informed consent and to determine whether these attitudes varied by gender. Methods A quantitative methodology was adopted for this study. Questions were scored using a Likert-type scale and face-to-face interviews were conducted with 610 refugees who had migrated to Turkey from MENA (Middle East and North Africa) countries. Results Refugees from eleven countries participated in the survey, of whom the majority were men (62.5% male versus 37.5% female). Reasons for migration include war/security, poverty, and persecution (67.3%), and wanting to live in developed countries (81.1%). The decision to migrate was mainly decided upon either solely by males (as stated by 46.1% of participants) or by the family as a whole (39.0%). Regarding competence in spoken Turkish, most participants (58.5%) were judged to be at a moderate level. A plurality preferred to follow their doctor’s advice for treatment (42.6%), while nearly one-third deferred to the male authority figure in the family (33.1%). A majority stated that they were unaware of the concept of informed consent (63.3%). There was a significant difference between the responses of men and women with respect to the eight questions concerning informed consent. Conclusion Autonomy is a fundamental principle of human rights and medical ethics. Refugees from MENA countries, where the concept of autonomy is contrary to deeply-help traditional religious views of much of the population, in general, have a poor grasp of informed consent as a patient right. Traditional religious/cultural values steeped in patriarchy constitute an obstacle to women making decisions regarding their own lives in MENA countries. Therefore, the practice of informed consent is of critical importance in helping to reduce gender differentials in health care.

scholarly journals The impact of a new genus on the molecular phylogeny of Hemisphaeriini (Hemiptera, Fulgoromorpha, Issidae)

ZooKeys ◽  
2019 ◽  
Vol 880 ◽  
pp. 61-74 ◽  
Author(s):  
Songping Zhao ◽  
Thierry Bourgoin ◽  
Menglin Wang
Keyword(s):  
Molecular Phylogeny ◽  
Molecular Analysis ◽  
Molecular Basis ◽  
New Genus ◽  
Guangxi Province ◽  
The Family ◽  
The Impact

A new genus, Retaldargen. nov. of the family Issidae (Hemisphaeriinae, Hemisphaeriini) is described from Guangxi Province of China. A revised molecular analysis for the Hemisphaeriini based on partial sequences of 18S, 28S, COXI and Cytb, provides evidence for a new lineage within the subtribe Mongolianina. With two subgroups of genera now identified, the monophyly of Mongolianina is discussed from both a morphological and a molecular basis.

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