Differential effects of zinc binding on structured and disordered regions in the multidomain STIL protein

Amartely, Hadar; David, Ahuvit; Shamir, Mai; Lebendiker, Mario; Izraeli, Shai; Friedler, Assaf

doi:10.1039/c6sc00115g

Cited by 4 publications

(2 citation statements)

References 47 publications

(53 reference statements)

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“…Likewise, 18 peptides (FSKASKNFSIKRSSQ, IKRSSQKLSSGKMPI, KLSSGKMPIHDHDSG, PIPSPHPVSQKISKI, ENPPLINHLEHLKPL, NHLEHLKPLQPQLYD, GIPNQLNQDKPALLR, KPALLRHCKVRQPPA, HCKVRQPPAYKKGNP, YKKGNPHTRNSIKPS, HTRNSIKPSSHNGPS, QNEEYPIRPSTLNSR, PHDFVFSPHNSGRPM, PPLPSYCSTNVCRCC, NVCRCCQHHSHIQYS, QHHSHIQYSPLNSWQ, DVQSEALQKHSLFHP, and YCNAFCSSSSPIALR) were submitted as query proteins to ZINCCLUSTER. These peptides were already analyzed by experimental methods by Amartely et al which is shown in their supporting information and confirmed that all the amyloid peptides bind with zinc except FSKASKNFSIKRSSQ, IKRSSQKLSSGKMPI. C‐score of all these eighteen peptides were predicted from ZINCCLUSTER and it is shown in Table , where C‐score values of all amino acids were below zero for the peptides FSKASKNFSIKRSSQ and IKRSSQKLSSGKMPI.…”

Section: Resultssupporting

confidence: 57%

Development of METAL‐ACTIVE SITE and ZINCCLUSTER tool to predict active site pockets

Ajitha

Sundar

Mugilan³

et al. 2018

Proteins

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The advent of whole genome sequencing leads to increasing number of proteins with known amino acid sequences. Despite many efforts, the number of proteins with resolved three dimensional structures is still low. One of the challenging tasks the structural biologists face is the prediction of the interaction of metal ion with any protein for which the structure is unknown. Based on the information available in Protein Data Bank, a site (METALACTIVE INTERACTION) has been generated which displays information for significant high preferential and low-preferential combination of endogenous ligands for 49 metal ions. User can also gain information about the residues present in the first and second coordination sphere as it plays a major role in maintaining the structure and function of metalloproteins in biological system. In this paper, a novel computational tool (ZINCCLUSTER) is developed, which can predict the zinc metal binding sites of proteins even if only the primary sequence is known. The purpose of this tool is to predict the active site cluster of an uncharacterized protein based on its primary sequence or a 3D structure. The tool can predict amino acids interacting with a metal or vice versa. This tool is based on the occurrence of significant triplets and it is tested to have higher prediction accuracy when compared to that of other available techniques.

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Section: Resultssupporting

confidence: 57%

Development of METAL‐ACTIVE SITE and ZINCCLUSTER tool to predict active site pockets

Ajitha

Sundar

Mugilan³

et al. 2018

Proteins

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show abstract

“…However, the molecular mechanism by which the tetramerization regulates centriole assembly is unclear. Previously, we have shown that STIL also undergoes higher-order oligomerization through its IDR upon binding to Zn 2+ ions together with a structural change of its NTD (residues 2-370, Figure 1A) [16]. Inhibition of STIL oligomerization through its CCD and/or IDR is a promising new potential target for cancer therapy.…”

Section: Introductionmentioning

confidence: 86%

Molecular Mechanism of STIL Coiled-Coil Domain Oligomerization

Shamir,

Martin,

Woolfson

et al. 2023

IJMS

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Coiled-coil domains (CCDs) play key roles in regulating both healthy cellular processes and the pathogenesis of various diseases by controlling protein self-association and protein–protein interactions. Here, we probe the mechanism of oligomerization of a peptide representing the CCD of the STIL protein, a tetrameric multi-domain protein that is over-expressed in several cancers and associated with metastatic spread. STIL tetramerization is mediated both by an intrinsically disordered domain (STIL400–700) and a structured CCD (STIL CCD718–749). Disrupting STIL oligomerization via the CCD inhibits its activity in vivo. We describe a comprehensive biophysical and structural characterization of the concentration-dependent oligomerization of STIL CCD peptide. We combine analytical ultracentrifugation, fluorescence and circular dichroism spectroscopy to probe the STIL CCD peptide assembly in solution and determine dissociation constants of both the dimerization, (KD = 8 ± 2 µM) and tetramerization (KD = 68 ± 2 µM) of the WT STIL CCD peptide. The higher-order oligomers result in increased thermal stability and cooperativity of association. We suggest that this complex oligomerization mechanism regulates the activated levels of STIL in the cell and during centriole duplication. In addition, we present X-ray crystal structures for the CCD containing destabilising (L736E) and stabilising (Q729L) mutations, which reveal dimeric and tetrameric antiparallel coiled-coil structures, respectively. Overall, this study offers a basis for understanding the structural molecular biology of the STIL protein, and how it might be targeted to discover anti-cancer reagents.

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Zinc-mediated Reversible Multimerization of Hsp31 Enhances the Activity of Holding Chaperone

Kim

Choi

Cha

et al. 2018

Journal of Molecular Biology

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Differential effects of zinc binding on structured and disordered regions in the multidomain STIL protein

Abstract: Here we show that simultaneous binding of Zn2+ ions has different effects on structured and disordered domains in the same multidomain protein.

Cited by 4 publications

References 47 publications

Development of METAL‐ACTIVE SITE and ZINCCLUSTER tool to predict active site pockets

Development of METAL‐ACTIVE SITE and ZINCCLUSTER tool to predict active site pockets

Molecular Mechanism of STIL Coiled-Coil Domain Oligomerization

Zinc-mediated Reversible Multimerization of Hsp31 Enhances the Activity of Holding Chaperone

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