Irene Hunter

University of Aberdeen

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Co-Authors

Iain J. McEwan

University of Aberdeen

Graeme F. Nixon

University of Aberdeen

David Skerrow

University of Glasgow

Konrad Beck

Lawrence Livermore National Laboratory

Therese Schulthess

University of Basel

Craig Jamieson

University of Strathclyde

Fiona A. Mathieson

University of Aberdeen

BÖ

Björn Öbrink

Karolinska Institutet

Jürgen Engel

University of Basel

C. R. M. Hay

Memorial Hermann Institute for Rehabilitation and Research Foundation

Cooperative Institutions

University of Aberdeen

Institute for Research in Biomedicine

Institute of Medical Sciences

Institute for Research in Biomedicine

University of Edinburgh

Tongji University

Shanghai Jiao Tong University

University of Glasgow

University of Strathclyde

Universitat Politècnica de Catalunya

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Evidence for a specific mechanism of laminin assembly

European Journal of Biochemistry (1990)

Irene Hunter Therese Schulthess M Bruch Konrad Beck Jürgen Engel

The specificity of laminin chain assembly was investigated using fragments E8 and C8–9, derived from the long arm of the molecule, whose rod‐like domain consists of the α‐helical regions of the A, B1 and B2 chains. Urea‐induced chain separation and unfolding were monitored by transverse urea/polyacrylamide gel electrophoresis (PAGE) and circular dichroism. Separation of the A and disulphide‐linked B1‐B2 chains occurred at 3.5–4.0 M urea and by 7.0 M urea all residual α‐helicity was lost. Removal of urea by dialysis resulted in high recoveries (87–100%) of renatured protein which in its apparent molecular mass, α‐helix content, chain composition, degree of association and ultrastructural appearance was indistinguishable from native E8. Reduction or reduction and alkylation of the chains did not lead to a decrease in their ability to reassemble specifically. Reformation of the single interchain disulphide, linking the B1 and B2 chains, clearly demonstrates that these chains are correctly aligned in parallel and in register in E8 renatured from its reduced chains. Renaturation of E8 from its reduced and alkylated chains precludes a role for disulphide formation in determining chain alignment but suggests rather that it is involved in the stabilisation of the correctly assembled molecule. These results, together with recent sequence data, provide evidence for the interaction of the α‐helical regions of the A, B1 and B2 chains in the formation of a triple coiled‐coil within the long arm of the molecule. The highly specific nature of this interaction suggests that it is the mechanism by which laminin is assembled in vivo .

Side chain

Coiled coil

Folding (DSP implementation)

10.1111/j.1432-1033.1990.tb15391.x

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Citations (47)

Evidence for regulated dimerization of cell-cell adhesion molecule (C-CAM) in epithelial cells

Biochemical Journal (1996)

Irene Hunter Hiroki Sawa Magnus Edlund Björn Öbrink

C-CAM is a Ca(2+)-independent cell adhesion molecule (CAM) belonging to the immunoglobulin superfamily. Addition of chemical cross-linkers to isolated rat liver plasma membranes, intact epithelial cells and purified preparations of C-CAM stabilized one major C-CAM-containing product whose apparent molecular mass was approximately twice that of the C-CAM monomer. The failure to detect additional proteins after cleavage of the cross-linked species demonstrated that C-CAM exists as non-covalently linked dimers both in solution and on the cell surface. Dimerization occurred to the same extent in adherent monolayers and in single cell populations, indicating that dimer formation was the result of cis-interactions within the membranes of individual cells. Using isoform-specific anti-peptide antibodies, both C-CAM1 and C-CAM2 were found to be involved in dimerization, forming predominantly homo-dimeric species. Both calmodulin and Ca2+ ionophore modulated the level of dimer formation, suggesting a role for regulated self-association in the functional activity of C-CAM.

Cleavage (geology)

Immunoglobulin superfamily

Cell membrane

10.1042/bj3200847

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Citations (63)

Laminin chain assembly by triple and double stranded coiled-coil structures.

Journal of Biological Chemistry (1992)

Irene Hunter Therese Schulthess J. Engel

We have previously provided evidence that laminin assembly occurs by the specific interaction of the alpha-helical domains of the A, B1, and B2 chains, located within the long arm of the molecule (Hunter, I., Schulthess, T., Bruch, M., Beck, K., and Engel, J. (1990) Eur. J. Biochem. 188, 205-211). Recent evidence for noncoordinate synthesis of the laminin chains, and in particular, the absence of the 400-kDa A chain from laminins produced by a number of cell types, has led us to examine the molecular mechanism of laminin assembly using the isolated A and B1-B2 chains of laminin fragment E8. E8A shows little tendency to self-associate, and when renatured from urea forms globular structures with little detectable alpha-helix. In contrast, E8B1-B2 renatures to form rod-like molecules, 30 nm in length. The rod-like structure, high alpha-helix content, and sharp thermal transition indicate that they are double stranded coiled coils. When mixed in equimolar amounts, E8A and E8B1-B2 renature to form molecules which are biochemically and ultrastructurally indistinguishable from native E8. If E8A and E8B1-B2 are renatured separately and mixed at a 1:1 molar ratio, they also form E8 molecules. These results suggest a mechanism of laminin assembly which involves the formation of a double coiled-coil B1-B2 intermediate with which the A chain subsequently interacts to form a triple coiled-coil laminin molecule. In addition, our results indicate that isoforms consisting of the B1 and B2 chains only would form stable laminin-like structures.

Coiled coil

Chain (unit)

Polypeptide chain

10.1016/s0021-9258(18)42654-3

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Citations (62)

Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain

ACS Medicinal Chemistry Letters (2023)

Martyn C. Henry Christopher M. Riley Irene Hunter J Mark Elwood J. Daniel Lopez‐Fernandez

The androgen receptor (AR) is central to prostate cancer pathogenesis and has been extensively validated as a drug target. However, small-molecule anti-androgen therapies remain limited due to resistance and will eventually fail to suppress tumor growth, resulting in progression to castration-resistant prostate cancer (CRPC). The intrinsically disordered N-terminal domain (NTD) is crucial for AR transactivation and has been investigated as a suitable target in the presence of ligand binding domain mutations. A screening campaign identified biaryl isoxazole compound

Enzalutamide

10.1021/acsmedchemlett.3c00426

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Citations (3)

The proteins of normal and psoriatic human epidermis

Irene Hunter

The epidermal fibrous protein has been successfully extracted from the cornified cells of human plantar callus and stratum corneum with buffered urea solutions. The proteins of these two horny cell layers are structurally dissimilar and differ also from the fibrous proteins prekeratin, of the living cell layers. Human prekeratin is a multichain protein, and on polyacrylamide gels, three different polypeptide chains of molecular weights 70,000, 63,000 and 55,000 can be detected. All three of these chains are present in plantar callus, but there is a much higher proportion of the 70,000 molecular weight chain than in purified prekeratin. The 55,000 molecular weight chain is not present in stratum corneum. The polypeptide chains of the fibrous protein are the major constituents of both living and horny cell layers 5, but in extracts of foreskin epidermis a prominent pale-blue staining polypeptide has been detected. It has a molecular weight of 45,000 and is apparently unrelated to any previously extracted epidermal protein. The 55,000 and 63,000 molecular weight chains of the fibrous protein are prominent in psoriatic scales, but the 70,000 molecular weight chain is deficient and occasionally absent. The psoriatic fibrous protein is structurally abnormal resembling neither the protein of callus nor stratum corneum. Effective treatment of psoriasis causes changes in the fibrous protein, finally resulting in a normal structure. The uninvolved callus and stratum corneum of psoriatics have fibrous protein structures indistinguishable from those of the normal tissues. There is an overall similarity between the amino acid analyses of callus, stratum corneum, psoriatic scale and human prekeratin, apart from differences in their contents of glycine and serine. Differences in the tissue contents of these two amino acids appear to be related to changes in the intensity of the 70,000 molecular weight chain of the fibrous protein. Varying the conditions of extraction of the horny cell layers alters the amount hut not the polypeptide composition of the isolated material. In the absence of a reducing agent, a large amount of fibrous protein polypeptides are released from psoriatic scale but only a very small amount from plantar callus. These results are discussed in relation to normal keratinisation and to the defects in this process in psoriatic epidermis.

Epidermis (zoology)

Corneocyte

Source

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The effect of increased tissue turnover on the keratinization of human epidermis☆

Biochimica et Biophysica Acta (BBA) - General Subjects (1981)

Irene Hunter David Skerrow

Epidermis (zoology)

Persistence (discontinuity)

Corneocyte

10.1016/0304-4165(81)90357-3

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Citations (26)

The potential roles of sphingolipids in vascular smooth-muscle function

Biochemical Society Transactions (2007)

Graeme F. Nixon Fiona A. Mathieson Irene Hunter

Increasing experimental evidence has demonstrated that sphingolipids are likely to have an important regulatory function in the cardiovascular system. Two sphingolipids released from activated platelets, and therefore of particular relevance, are S1P (sphingosine 1-phosphate) and SPC (sphingosylphosphocholine). Both S1P and SPC can act as vasoconstrictors and may modulate VSMC (vascular smooth muscle cell) phenotype, as observed during the pathogenesis of vascular disease. Recent research has suggested that SPC may act as a pro-inflammatory mediator in VSMCs and, in some circumstances, may also contribute to the development of vascular disease.

Sphingolipid

Mediator

Pathogenesis

Mural cell

10.1042/bst0350908

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Citations (6)

Codon Usage in Acinetobacter Structural Genes

Springer eBooks (1991)

Philip J. White Irene Hunter C. A. Fewson

Coding region

10.1007/978-1-4899-3553-3_17

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Citations (13)

The androgen receptor amino-terminal domain: structure, function and therapeutic potential

Endocrine Oncology (2025)

Irene Hunter Craig Jamieson Iain J. McEwan

Signalling by the steroid hormone testosterone involves the androgen receptor (AR), a structurally dynamic protein. The amino-terminal domain of the AR makes up more than half of the protein and has been found to be intrinsically disordered. This structural plasticity mediates receptor-dependent transcription, intradomain interactions and allosteric regulation. AR activity is a primary drug target in advanced and metastatic prostate cancer, a leading cause of cancer-related death in men. Recent research has focused on the amino-terminal domain as a novel drug target. In this review, we discuss the structural properties of the receptor and highlight some promising preclinical and clinical studies that aim to develop a drug discovery pipeline of small molecule inhibitors targeting the amino-terminal domain.

Amino terminal

10.1530/eo-24-0061

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