Dynamic Regulation of α-Actinin’s Calponin Homology Domains on F-Actin

Shams, Hengameh; Golji, Javad; Garakani, Kiavash; Mofrad, Mohammad R. K.

doi:10.1016/j.bpj.2016.02.024

Cited by 23 publications

(29 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 B for Utr ABD1). This is in agreement with the recent work of Shams et al (40), which suggests that various binding modes between ABD1 and actin could be accessible. Therefore, the conformational ensembles computationally characterized could explain how both compact and extended conformations of ABD1 are sampled when bound to actin.…”

Section: Discussionsupporting

confidence: 93%

Dynamics of Dystrophin’s Actin-Binding Domain

Fealey

Horn

Coffman

et al. 2018

Biophysical Journal

View full text Add to dashboard Cite

We have used pulsed electron paramagnetic resonance, calorimetry, and molecular dynamics simulations to examine the structural mechanism of binding for dystrophin's N-terminal actin-binding domain (ABD1) and compare it to utrophin's ABD1. Like other members of the spectrin superfamily, dystrophin's ABD1 consists of two calponin-homology (CH) domains, CH1 and CH2. Several mutations within dystrophin's ABD1 are associated with the development of severe degenerative muscle disorders Duchenne and Becker muscular dystrophies, highlighting the importance of understanding its structural biology. To investigate structural changes within dystrophin ABD1 upon binding to actin, we labeled the protein with spin probes and measured changes in inter-CH domain distance using double-electron electron resonance. Previous studies on the homologous protein utrophin showed that actin binding induces a complete structural opening of the CH domains, resulting in a highly ordered ABD1-actin complex. In this study, double-electron electron resonance shows that dystrophin ABD1 also undergoes a conformational opening upon binding F-actin, but this change is less complete and significantly more structurally disordered than observed for utrophin. Using molecular dynamics simulations, we identified a hinge in the linker region between the two CH domains that grants conformational flexibility to ABD1. The conformational dynamics of both dystrophin's and utrophin's ABD1 showed that compact conformations driven by hydrophobic interactions are preferred and that extended conformations are energetically accessible through a flat free-energy surface. Considering that the binding free energy of ABD1 to actin is on the order of 6-7 kcal/mole, our data are compatible with a mechanism in which binding to actin is largely dictated by specific interactions with CH1, but fine tuning of the binding affinity is achieved by the overlap between conformational ensembles of ABD1 free and bound to actin.

show abstract

Section: Discussionsupporting

confidence: 93%

Dynamics of Dystrophin’s Actin-Binding Domain

Fealey

Horn

Coffman

et al. 2018

Biophysical Journal

View full text Add to dashboard Cite

show abstract

“…Cryo-electron microscopy data revealed that the CH1 domain of human filamin A contributed to F-actin binding without direct CH2 and actin interactions (Iwamoto et al, 2018). Binding of the CH1-CH2 domain and actin is mechanically regulated via closed or open conformations (Shams et al, 2016). The CH1 domain contains the main actin-binding sites, however, one of the binding sites of CH1 is buried within the CH1-CH2 interface and only becomes accessible in the open conformation (Borrego-Diaz et al, 2006).…”

Section: Binding With Actin and Tubulinmentioning

confidence: 99%

Structural Characteristics, Binding Partners and Related Diseases of the Calponin Homology (CH) Domain

Yin

Schnoor

Jun

2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The calponin homology (CH) domain is one of the most common modules in various actin-binding proteins and is characterized by an α-helical fold. The CH domain plays important regulatory roles in both cytoskeletal dynamics and signaling. The CH domain is required for stability and organization of the actin cytoskeleton, calcium mobilization and activation of downstream pathways. The CH domain has recently garnered increased attention due to its importance in the onset of different diseases, such as cancers and asthma. However, many roles of the CH domain in various protein functions and corresponding diseases are still unclear. Here, we review current knowledge about the structural features, interactome and related diseases of the CH domain.

show abstract

“…Several mutations of this gene have been found, and it usually correlates with abnormal serum levels and the function of α-actinin-4, especially in those patients suffering with FSGS [4]. e presence of the ACTN4 gene p.Lys255Glu mutation relates to abnormal affinity of the actin-binding domain (ABD), which is mainly due to conformational changes in the molecular structure of α-actinin-4 [5,6]. An Y265H variant of the ACTN4 gene has also been detected in an adolescent patient with FSGS [7].…”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel ACTN4 Gene Mutation Which Is Resistant to Primary Nephrotic Syndrome Therapy

Meng

Cao

Lin

et al. 2019

BioMed Research International

View full text Add to dashboard Cite

ACTN4, a gene which codes for the protein α-actinin-4, is critical for the maintenance of the renal filtration barrier. It is well known that ACTN4 mutations can lead to kidney dysfunction, such as familial focal segmental glomerulosclerosis (FSGS), a common cause of primary nephrotic syndrome (PNS). To elucidate whether other mutations of ACTN4 exist in PNS patients, we sequenced the ACTN4 gene in biopsies collected from 155 young PNS patients (≤16 years old). The patients were classified into five groups: FSGS, minimal change nephropathy, IgA nephropathy, membranous nephropathy, and those without renal puncture. Ninety-eight healthy people served as controls. Samples were subjected to Illumina’s next generation sequencing protocols using FastTarget target gene capture method. We identified 5 ACTN4 mutations which occurred only in PNS patients: c.1516G > A (p.G506S) on exon 13 identified in two PNS patients, one with minimal change nephropathy and another without renal puncture; c.1442 + 10G > A at the splice site in a minimal change nephropathy patient; c.2191-4G > A at the cleavage site, identified from two FSGS patients; and c.1649A > G (p.D550G) on exon 14 together with c.2191-4G > A at the cleavage sites, identified from two FSGS patients. Among these, c.1649A > G (p.D550G) is a novel ACTN4 mutation. Patients bearing the last two mutations exhibited resistance to clinical therapies.

show abstract

Dynamic Regulation of α-Actinin’s Calponin Homology Domains on F-Actin

Cited by 23 publications

References 50 publications

Dynamics of Dystrophin’s Actin-Binding Domain

Dynamics of Dystrophin’s Actin-Binding Domain

Structural Characteristics, Binding Partners and Related Diseases of the Calponin Homology (CH) Domain

Identification of a Novel ACTN4 Gene Mutation Which Is Resistant to Primary Nephrotic Syndrome Therapy

Contact Info

Product

Resources

About