Non-syndromic Mitral Valve Dysplasia Mutation Changes the Force Resilience and Interaction of Human Filamin A

Haataja, Tatu; Bernardi, Rafael C.; Lecointe, Simon; Capoulade, Romain; Mérot, Jean; Pentikäinen, Ulla

doi:10.1016/j.str.2018.09.007

Cited by 15 publications

(21 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The directionality of forces can regulate key biological activities. For instance, some genetic diseases cause mutations in mechanoactive proteins that, in turn, lead to notable phenotypic differences in humans (2). In a simulation study, Best et al (3) investigated the unfolding of a small protein domain for different pulling directions.…”

Section: Introductionmentioning

confidence: 99%

Streptavidin/biotin: Tethering geometry defines unbinding mechanics

et al. 2020

Self Cite

View full text Add to dashboard Cite

Macromolecules tend to respond to applied forces in many different ways. Chemistry at high shear forces can be intriguing, with relatively soft bonds becoming very stiff in specific force-loading geometries. Largely used in bionanotechnology, an important case is the streptavidin (SA)/biotin interaction. Although SA’s four subunits have the same affinity, we find that the forces required to break the SA/biotin bond depend strongly on the attachment geometry. With AFM-based single-molecule force spectroscopy (SMFS), we measured unbinding forces of biotin from different SA subunits to range from 100 to more than 400 pN. Using a wide-sampling approach, we carried out hundreds of all-atom steered molecular dynamics (SMD) simulations for the entire system, including molecular linkers. Our strategy revealed the molecular mechanism that causes a fourfold difference in mechanical stability: Certain force-loading geometries induce conformational changes in SA’s binding pocket lowering the energy barrier, which biotin has to overcome to escape the pocket.

show abstract

Section: Introductionmentioning

confidence: 99%

Streptavidin/biotin: Tethering geometry defines unbinding mechanics

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…These data indicate that unfolding of Ig domain requires over 50pN force, whereas dissociation of domain pairs occurs by physiologically relevant force. FLNA R3-R5 in the rod-1 forms domain pairs but dissociation of these domain pairs may require over 50pN or may be below the measurement limit [29,147,153]. The mechanical properties of the FLNC molecule has never been investigated.…”

Section: Mechanotransductionmentioning

confidence: 99%

Structure and Function of Filamin C in the Muscle Z-Disc

Mao

Nakamura

2020

IJMS

View full text Add to dashboard Cite

Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres. Since phosphorylation of FLNC by PKC diminishes the calpain sensitivity, assembly, and disassembly of the Z-disc may be regulated by phosphorylation of FLNC. Mutations of FLNC result in cardiomyopathy and muscle weakness. Although this review will focus on the current understanding of FLNC structure and functions in muscle, we will also discuss other filamins because they share high sequence similarity and are better characterized. We will also discuss a possible role of FLNC as a mechanosensor during muscle contraction.

show abstract

“…For example, the packing of repeat domains 3, 4, and 5 allows for the stabilization of ligand binding to repeat 4 (Ithychanda et al, 2009; Sethi et al, 2014) while also adding to the mechanical resilience of rod domain‐1. Both characteristics may be disrupted by pathogenic variation within repeat 5 (Haataja, Bernardi, et al, 2019; Haataja, Capoulade, et al, 2019; Figure 1B). Another example is the tight interaction between repeat domains 16 and 17 of FLNA and FLNB that requires shear force, such as that experienced by endothelial cells lining the blood vessels, or perhaps a competing ligand to unravel.…”

Section: Flna Its Transcripts and Proteinsmentioning

confidence: 99%

“…FLNA and its interactors, including the possible modification of FLNA by serotonin, are essential for the organization of the ECM by interstitial cells (Sauls et al, 2012). Recently it has been shown in computer simulations that the mitral valve dysplasia variant p.Pro637Gln enables repeats 4 and 5 to be pulled apart from one another with significantly less force than the wild‐type protein (Haataja, Bernardi, et al, 2019). This mechanism has subsequently been confirmed experimentally by the same group for two disease causing variants p.Val711Asp and p.His743Pro.…”

Section: Familial Cardiac Myxomatous Polyvalvular Dystrophymentioning

confidence: 99%

The X‐linked filaminopathies: Synergistic insights from clinical and molecular analysis

et al. 2020

View full text Add to dashboard Cite

The X-linked filaminopathies represent a diverse group of clinical conditions, all caused by variants in the gene FLNA. FLNA encodes the widely expressed actin binding protein, filamin A that has multiple roles during embryonic development including cell migration, mechanical sensing, and cell signaling. In this review, we discuss the 10 distinct X-linked filaminopathy conditions that between them affect almost all organ systems, including the brain, skeleton, heart, and skin, highlighting the critical role of this protein in human development. We review each of the phenotypes and discuss their pathogenesis, where known. Assigning pathogenicity to variants in FLNA can prove difficult, especially for missense variants and small indels, in-part because of the X-linked nature of the phenotypes, the overlap of phenotypic features between conditions, and poor understanding of the function of certain protein domains. We outline here approaches to characterize phenotypes, highlight hotspot regions within FLNA commonly mutated in these conditions, and approaches to resolving some variants of uncertain significance. K E Y W O R D S filamin A, filaminopathy, periventricular nodular heterotopia, skeletal dysplasia, X-linked disease 1 | INTRODUCTION Pathogenic variants in FLNA, the X-linked gene that encodes the cytoskeletal protein filamin A (FLNA), cause a diverse spectrum of genetic syndromes with features ranging from impaired brain development to skeletal dysplasias, gastrointestinal disorders, and compromised structure and function of the cardiac valves. To date, eight discrete syndromes are formally associated with variants in FLNA reported in OMIM (MIM# 300017). These are X-linked cardiac valvular dysplasia, congenital short bowel syndrome (also called X-linked congenital idiopathic intestinal pseudo-obstruction), frontometaphyseal dysplasia type I, periventricular nodular heterotopia (PH), Melnick -needles syndrome (MNS), otopalatodigital syndrome type 1 (OPD1), OPD2, and digitocutaneous dysplasia (DCD; formally terminal osseous dysplasia). At least two more entities should be added to this list, isolated thrombocytopenia (Nurden et al., 2011) and a disorder characterized by keloid scarring, joint contractures, and cardiac valvulopathy (Atwal et al., 2016; Lah et al., 2015). Collectively, these conditions have been termed the X-linked filaminopathies.The broad diversity of organ systems affected across this phenotypic spectrum highlight the pivotal role that FLNA plays in human development and its widespread, but not quite ubiquitous, expression (Fox et al., 1998;Robertson et al., 2003Robertson et al., , 2007. Additionally, due to the X chromosomal location of FLNA, the presentation of FLNArelated phenotypes varies between males and females. These factors conspire to make the clinical and molecular diagnosis of FLNA-related disorders challenging.Here, we review the phenotypes associated with mutations in FLNA with emphasis on those that have been newly described since the previous comprehensive review on filaminopat...

show abstract

Non-syndromic Mitral Valve Dysplasia Mutation Changes the Force Resilience and Interaction of Human Filamin A

Cited by 15 publications

References 59 publications

Streptavidin/biotin: Tethering geometry defines unbinding mechanics

Streptavidin/biotin: Tethering geometry defines unbinding mechanics

Structure and Function of Filamin C in the Muscle Z-Disc

The X‐linked filaminopathies: Synergistic insights from clinical and molecular analysis

Contact Info

Product

Resources

About