Exploring protein interiors: The role of a buried histidine in the KH module fold

Fraternali, Franca; Amodeo, Pietro; Musco, Giovanna; Nilges, Michaël; Pastore, Annalisa

doi:10.1002/(sici)1097-0134(19990301)34:4<484::aid-prot8>3.0.co;2-p

Cited by 15 publications

(17 citation statements)

References 33 publications

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“…In Family TSRVD001, a C39453T mutation (exon 37, Thr2896Ile, Figure 2 and Figure 3) 13, 28, 29 showed complete segregation of the mutation with the ARVC phenotype in six affected individuals (Figure 1). 14, 16 The Thr2896Ile mutation, absent in all other tested families and controls, was shared by two fifth degree relatives with ARVC (III-1 and V-5) providing strong genetic evidence that this TTN mutation is linked to the ARVC phenotype.…”

Section: Resultsmentioning

confidence: 99%

Genetic Variation in Titin in Arrhythmogenic Right Ventricular Cardiomyopathy–Overlap Syndromes

et al. 2011

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Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin (TTN) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin protein to the transitional junction at intercalated disks. Methods and Results All 312 titin exons known to be expressed in human cardiac titin and the complete 3’ untranslated region were sequenced in 38 ARVC families. Eight unique TTN variants were detected in 7 families including a prominent Thr2896Ile mutation that showed complete segregation with the ARVC phenotype in one large family. The Thr2896IIe mutation maps within a highly conserved immunoglobulin-like fold (Ig10 domain), located in titin’s spring region. Native gel electrophoresis, NMR, intrinsic fluorescence, and proteolysis assays of wildtype and mutant Ig10 domains revealed that the Thr2896IIe exchange reduces the structural stability and increases the propensity towards degradation of the Ig10 domain. The phenotype of TTN variant carriers was characterized by history of sudden death (5/7 families), progressive myocardial dysfunction causing death or heart transplant (8/14 cases), frequent conduction disease (11/14), and incomplete penetrance (86%). Conclusions Our data provide evidence that titin mutations can cause ARVC, a finding that further expands the origin of the disease beyond desmosomal proteins. Structural impairment of the titin spring is a likely cause of ARVC and constitutes a novel mechanism underlying myocardial remodeling and sudden cardiac death.

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Section: Resultsmentioning

confidence: 99%

Genetic Variation in Titin in Arrhythmogenic Right Ventricular Cardiomyopathy–Overlap Syndromes

et al. 2011

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“…The work presented here offers a different approach from the ones used in ARIA and NOAH. [1][2][3][4][5][6] In these programs, the different assignments compete against each other in single molecular dynamics calculations. The incorrect NOEs are then identified based on the size of residual violation for that NOE.…”

Section: Discussionmentioning

confidence: 99%

“…These limitations stem from the nature of the problem and most likely affect both ARIA and NOAH. [1][2][3][4][5][6] First of all, the technique is path dependent, i.e., different starting points for the calculation will produce different final constraint sets. Nilges 1 has estimated that there are more than 10 350 constraint sets that can be constructed from the ambiguous NOEs for BPTI.…”

Section: Discussionmentioning

confidence: 99%

“…The use of the null_NOE distinguishes this approach from other techniques for assigning ambiguous. [1][2][3][4][5][6] The null_NOE is included because it is quite possible that none of the proposed assignments are correct. For example, the NOE could belong to an unassigned proton resonance or possibly a minor conformational isomer.…”

Section: Creating a New Generation Of Structuresmentioning

confidence: 99%

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Modified genetic algorithm resolves ambiguous NOE restraints and reduces unsightly NOE violations

Adler¹

2000

Proteins

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In an ideal world, every NOE cross peak would have a unique assignment. However, the interpretation of NOE peaks is frequently complicated by overlapping resonances. In theory, ambiguous assignments could be resolved by performing separate structure calculations with each possible interpretation. Unfortunately, this would require an astronomical amount of computing time. A modified genetic algorithm has been developed that efficiently resolves hundreds of ambiguous restraints in parallel. Each NOE assignment becomes a gene that can be passed on to a new generation. New individuals are constructed by making a constraint lists from a subset of the genes. The constraint lists are then tested for self-consistency by using molecular dynamics to generate new structures for each list. To a first-degree approximation, there is enough information retained in each list to determine the global fold of the protein. Self-consistent constraint lists receive higher scores and their genes (or NOEs) stand a better chance of surviving into the next generation. The process selects NOEs that are consistent with the global fold. Under normal conditions, the program converges in 3 to 8 generations using 70 structures per generation. The final constraints are self-consistent and contain almost no residual NOE violations.

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“…fmr1-KH. 53 This behavior has been correlated to the presence in vig-KH6 and in all the other KH modules in vigilin of a conserved histidine that is otherwise replaced by a hydrophobic residue in most of the family. The histidine is buried in the structure and surrounded by other residues which are part of the hydrophobic core.…”

Section: Stability Of the Kh Domainmentioning

confidence: 97%

Novel RNA‐binding motif: The KH module

Adinolfi¹,

Bagni

Morelli

et al. 1999

Biopolymers

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The KH motif has recently been identified in single or multiple copies in a number of RNA associated proteins. Here we review the current knowledge accumulated about the sequence, structure, and functions of the KH. The multidomain architecture of most of the KH-containing proteins inspired an approach based on the production of peptides spanning the sequence of an isolated KH motif. Correct identification of the minimal length necessary for producing a folded peptide has had a number of important consequences for interpreting functional data. The presence of the KH motifs in fmr1, the protein responsible for the fragile X syndrome, and their possible role in the fmr1 functions are also discussed.

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Exploring protein interiors: The role of a buried histidine in the KH module fold

Abstract: The K-homology (

Cited by 15 publications

References 33 publications

Genetic Variation in Titin in Arrhythmogenic Right Ventricular Cardiomyopathy–Overlap Syndromes

Genetic Variation in Titin in Arrhythmogenic Right Ventricular Cardiomyopathy–Overlap Syndromes

Modified genetic algorithm resolves ambiguous NOE restraints and reduces unsightly NOE violations

Novel RNA‐binding motif: The KH module

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