Specific Amino Acid Substitutions Determine the Differential Contribution of the N- and C-terminal Domains of Insulin-like Growth Factor (IGF)-binding Protein-5 in Binding IGF-I

Shand, John H.; Beattie, James; Song, Hyuk; Phillips, Kirsten; Kelly, Sharon M.; Flint, David; Allan, Gordon J.

doi:10.1074/jbc.m300526200

Cited by 48 publications

(64 citation statements)

References 32 publications

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“…A series of engineered amino acid substitutions within the N-domain of IGFBP-5 (K68N, P69Q, L70Q, L73Q, L74Q) results in a nearly 100-fold decline in binding affinity for IGF-I and IGF-II (35,37). Despite this major perturbation in IGF binding capability, our results show that the disulfide-binding pattern of the cysteines flanking these mutations is not compromised.…”

Section: Discussionmentioning

confidence: 64%

“…Our results definitively identify 5 of 9 disulfide bonds in the protein, and determine that the other 4 linkages involve the four cysteines within the conserved GCGCCMTC motif (residues [32][33][34][35][36][37][38][39] in the N-terminal region of the protein.…”

mentioning

confidence: 74%

“…We analyzed this linkage in full-length IGFBP-5 and compared it to results obtained with a N-terminal domain amino acid substitution mutant involving residues K68N, P69Q, L70Q, L73Q, and L74Q to determine whether disruption of this disulfide bond might account for the diminished IGF binding affinity of the latter protein (35,37). Both wild type and N-mutant IGFBP-5 were digested with trypsin and subjected to the MS3 protocol (Fig.…”

Section: Amino Acid Substitution Mutations In the N-terminal Domain Omentioning

confidence: 99%

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Defining the Disulfide Bonds of Insulin-like Growth Factor-binding Protein-5 by Tandem Mass Spectrometry with Electron Transfer Dissociation and Collision-induced Dissociation

Nili¹,

Mukherjee

Shinde

et al. 2012

Journal of Biological Chemistry

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Background: Only 2 of 9 putative disulfide bonds have been mapped for IGFBP-5. Results: Using a MS-based strategy combining ETD and CID, and ab initio molecular modeling, we have mapped all 9 disulfide bonds in IGFBP-5. Conclusion: Our results provide new insights into the IGFBP-5 structure. Significance: We define an approach using tandem MS and ab initio molecular modeling to characterize unknown disulfide linkages in proteins.

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Section: Discussionmentioning

confidence: 64%

mentioning

confidence: 74%

Section: Amino Acid Substitution Mutations In the N-terminal Domain Omentioning

confidence: 99%

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Defining the Disulfide Bonds of Insulin-like Growth Factor-binding Protein-5 by Tandem Mass Spectrometry with Electron Transfer Dissociation and Collision-induced Dissociation

Nili¹,

Mukherjee

Shinde

et al. 2012

Journal of Biological Chemistry

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“…IGFBPs-1-6 share a high degree of similarity in their primary protein structure (identities approx. 30-40%), with highest conservation at the N-and C-terminal regions (Figures 6 and 7), which participate in binding to IGFs (Baxter, 2000;Payet et al, 2003;Shand et al, 2003). The structure of the N-terminal domain of IGFBP-5 discloses a rigid, globular fold that consists of a centrally located three-stranded antiparallel b-sheet (Zeslawski et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Proteolysis of insulin-like growth factor binding proteins (IGFBPs) by calpain

Ghosh

Shanker

Siwanowicz

et al. 2005

Biological Chemistry

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Calpains are non-lysosomal, Ca 2q -dependent cysteine proteases, which are ubiquitously distributed across cell types and vertebrate species. The rules that govern calpain specificity have not yet been determined. To elucidate the cleavage pattern of calpains, we carried out calpain-induced proteolytic studies on the insulin-like growth factor binding proteins IGFBP-4 and -5. Proteolysis of IGFBPs is well characterized in numerous reports. Our results show that calpain cleavage sites are in the non-conserved unstructured regions of the IGFBPs. Compilation of the calpain-induced proteolytic cleavage sites in several proteins reported in the literature, together with our present study, has not revealed clear preferences for amino acid sequences. We therefore conclude that calpains seem not to recognize amino acid sequences, but instead cleave with low sequence specificity at unstructured or solvent-exposed fragments that connect folded, stable domains of target proteins.

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“…An N-terminal domain of IGFBP-5 contains the IGF-1-binding region and caveolin-binding sites (10). The C-terminal domain does not bind IGF-1, but it can influence the IGF-1 binding affinity (11). A highly basic domain in the C-terminal end of IGFBP-5 (amino acids 201-218) has a functional nuclear localization sequence (12), yet secretion and reuptake of protein and possibly proteolytic processing appears to be required for nuclear translocation (13).…”

mentioning

confidence: 99%

Insulin-like Growth Factor-binding Protein-5-induced Laminin γ1 Transcription Requires Filamin A

Abrass

Hansen

2010

Journal of Biological Chemistry

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Insulin-like growth factor-binding proteins (IGFBPs) 2 modulate IGF-1 action by preventing IGF-1 degradation and by modulating IGF-1 receptor binding (1, 2), yet among the six IGFBP that bind IGF-1, IGFBP-3 and IGFBP-5 exhibit IGFindependent effects (3-6). IGFBP-5 has important effects on cell proliferation, apoptosis, migration, and regulation of transcription (7-9), which have been shown to be relevant to understanding cell differentiation, senescence, and cancer (3). An N-terminal domain of IGFBP-5 contains the IGF-1-binding region and caveolin-binding sites (10). The C-terminal domain does not bind IGF-1, but it can influence the IGF-1 binding affinity (11). A highly basic domain in the C-terminal end of IGFBP-5 (amino acids 201-218) has a functional nuclear localization sequence (12), yet secretion and reuptake of protein and possibly proteolytic processing appears to be required for nuclear translocation (13). Cellular reuptake can occur by several mechanisms that are attributed to the C-terminal domain including uptake by a protein transduction domain (14), binding to transferrin with subsequent uptake by the transferrin receptor (15), a possible IGFBP-5 receptor (6), or interaction with the type V transforming growth factor ␤ receptor (16). It is possible that each of these uptake mechanisms lead to different biological responses. Studies to understand the intranuclear effects of IGFBP-5 have revealed a cryptic domain in the N-terminal portion of the molecule that can act as a transcriptional transactivator (13). Amaar et al. (17) showed that IGFBP-5 201-218 binds to the second and third LIM domains of FHL2, and they proposed that IGFBP-5 participates in transcriptional regulation through binding to this transcriptional co-activator. IGFBP-5 also influences gene transcription through interaction with the retinoic acid receptor-rexinoid receptor system (18). Less is known about IGFBP-5 gene targets and other steps involved in transcriptional control by IGFBP-5.Filamin A (FLNa) is a 280-kDa protein with an N-terminal actin-binding domain followed by 24 repeats that are interrupted by two hinge regions and a C terminus that is responsible for dimerization (19). The hinge regions allow FLNa to function as a molecular leaf spring, lending flexibility and stiffness to the actin filaments (19) when FLNa participates in connections between the intracellular domain of integrins and the cytoskeleton. The 24 Ig-like repeats serve as docking sites for a variety of proteins that regulate cellular responses to growth factors and perturbants of cell-matrix attachments. Thus far, more than 20 FLNa binding partners have been described, and more have been proposed (20). Sites that bind the intracellular domains of integrins (21), the potassium channel, androgen receptor (22), calcium sensing receptor (23), and prostate-specific antigen (24) are near the C terminus (repeats 16 -24). Signal transduction molecules, such as the Rho GTPases (Rho/ Rac/cdc42), RalA, and Smads, bind in repeats 17-23 (25-28). Other proteins can...

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Specific Amino Acid Substitutions Determine the Differential Contribution of the N- and C-terminal Domains of Insulin-like Growth Factor (IGF)-binding Protein-5 in Binding IGF-I

Abstract: We have previously reported that two highly conserved amino acids in the C-terminal domain of rat insulin-like growth factor-binding protein (

Cited by 48 publications

References 32 publications

Defining the Disulfide Bonds of Insulin-like Growth Factor-binding Protein-5 by Tandem Mass Spectrometry with Electron Transfer Dissociation and Collision-induced Dissociation

Defining the Disulfide Bonds of Insulin-like Growth Factor-binding Protein-5 by Tandem Mass Spectrometry with Electron Transfer Dissociation and Collision-induced Dissociation

Proteolysis of insulin-like growth factor binding proteins (IGFBPs) by calpain

Insulin-like Growth Factor-binding Protein-5-induced Laminin γ1 Transcription Requires Filamin A

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