A Mechanism of Global Shape-dependent Recognition and Phosphorylation of Filamin by Protein Kinase A

Ithychanda, Sujay Subbayya; Mohan, Maradumane L; Zhu, Liang; Tirupula, Kalyan; Prasad, Sathyamangla V Naga; Wang, Yun Xing; Karnik, Sadashiva S.; Qin, Jun

doi:10.1074/jbc.m114.633446

Cited by 16 publications

(24 citation statements)

References 79 publications

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“…Release of autoinhibition of ligand binding sites within rod domain‐2 leads to phosphorylation of Ser2152 (NP_001104026.1) (Ithychanda et al, 2015) a proposed common pathway for many FLNA functions (Figure 1D). FLNA Ser2152 is a target for phosphorylation by numerous kinases including protein kinase A (PKA; Jay, Garcia, & de la Luz Ibarra, 2004), AKT (Ravid et al, 2008), PAK1 (Vadlamudi et al, 2002), and Ca 2+ /calmodulin‐dependent protein kinase II (Ohta & Hartwig, 1995).…”

Section: Flna Its Transcripts and Proteinsmentioning

confidence: 99%

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

et al. 2020

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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...

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Section: Flna Its Transcripts and Proteinsmentioning

confidence: 99%

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

et al. 2020

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“…The binding of ligands relieves autoinhibition, generating a conformation compatible as a substrate for PKA-mediated phosphorylation (17). This mechanism is a unique example of substrate shape-dependent phosphorylation by a kinase (17) (Fig. 1A).…”

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“…Cytoplasmic portions of many transmembrane proteins seem to be prime targets for filamin binding, mediating the physical linkage of these proteins with actin filaments for regulating cytoskeletal structure, cell shape, and cell migration (4,5). Among the 24 repeats of vertebrate filamins, 7 repeats (4,9,12,17,19,21, and 23) have a conserved "CD" groove in their immunoglobulin domain (Ig) that can accommodate an 11-13-residue-long amino acid segment of a binding partner protein (4). These ligands of filamin augment the immunoglobulin domain as a ␤-strand, thereby extending a ␤-sheet (5-9) (PDB: 2BP3, 2K9U, 2W0P, 2BRQ, and 3ISW).…”

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“…Non-phosphorylatable and phosphomimetic changes at this serine lead to perturbed focal adhesion formation and cell adhesion defects (15,16). The process of Ser-2152 phosphorylation is stringently regulated by the conformation of Ig repeats 20 and 21 (17). The intramolecular binding of the N-terminal residues of Ig20 to the ligand binding site on Ig21 creates autoinhibition that prevents Ig21 binding to external ligands (18) (PDB 2J3S).…”

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“…The intramolecular binding of the N-terminal residues of Ig20 to the ligand binding site on Ig21 creates autoinhibition that prevents Ig21 binding to external ligands (18) (PDB 2J3S). The binding of ligands relieves autoinhibition, generating a conformation compatible as a substrate for PKA-mediated phosphorylation (17). This mechanism is a unique example of substrate shape-dependent phosphorylation by a kinase (17) (Fig.…”

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Structural and thermodynamic basis of a frontometaphyseal dysplasia mutation in filamin A

Ithychanda

Dou

Robertson

et al. 2017

Journal of Biological Chemistry

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Filamin-mediated linkages between transmembrane receptors (TR) and the actin cytoskeleton are crucial for regulating many cytoskeleton-dependent cellular processes such as cell shape change and migration. A major TR binding site in the immunoglobulin repeat 21 (Ig21) of filamin is masked by the adjacent repeat Ig20, resulting in autoinhibition. The TR binding to this site triggers the relief of Ig20 and protein kinase A (PKA)-mediated phosphorylation of Ser-2152, thereby dynamically regulating the TR-actin linkages. A P2204L mutation in Ig20 reportedly cause frontometaphyseal dysplasia, a skeletal disorder with unknown pathogenesis. We show here that the P2204L mutation impairs a hydrophobic core of Ig20, generating a conformationally fluctuating molten globule-like state. Consequently, unlike in WT filamin, where PKA-mediated Ser-2152 phosphorylation is ligand-dependent, the P2204L mutant is readily accessible to PKA, promoting ligand-independent phosphorylation on Ser-2152. Strong TR peptide ligands from platelet GP1bα and G-protein-coupled receptor MAS effectively bound Ig21 by displacing Ig20 from autoinhibited WT filamin, but surprisingly, the capacity of these ligands to bind the P2204L mutant was much reduced despite the mutation-induced destabilization of the Ig20 structure that supposedly weakens the autoinhibition. Thermodynamic analysis indicated that compared with WT filamin, the conformationally fluctuating state of the Ig20 mutant makes Ig21 enthalpically favorable to bind ligand but with substantial entropic penalty, resulting in total higher free energy and reduced ligand affinity. Overall, our results reveal an unusual structural and thermodynamic basis for the P2204L-induced dysfunction of filamin and frontometaphyseal dysplasia disease.

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cAMP/PKA-induced filamin A (FLNA) phosphorylation inhibits SST2 signal transduction in GH-secreting pituitary tumor cells

et al. 2018

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A Mechanism of Global Shape-dependent Recognition and Phosphorylation of Filamin by Protein Kinase A

Cited by 16 publications

References 79 publications

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

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

Structural and thermodynamic basis of a frontometaphyseal dysplasia mutation in filamin A

cAMP/PKA-induced filamin A (FLNA) phosphorylation inhibits SST2 signal transduction in GH-secreting pituitary tumor cells

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