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Autosomal recessive cutis Laxa 1C mutations disrupt the structure and interactions of latent TGFβ binding protein-4

DOI: 10.3389/fgene.2021.706662 DOI Help

Authors: Yasmene F. Alanazi (University of Manchester) , Michael P. Lockhart-Cairns (University of Manchester) , Stuart A. Cain (University of Manchester) , Thomas A. Jowitt (University of Manchester) , Anthony S. Weiss (University of Sydney) , Clair Baldock (University of Manchester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Frontiers In Genetics , VOL 12

State: Published (Approved)
Published: September 2021
Diamond Proposal Number(s): 1580

Open Access Open Access

Abstract: Latent TGFβ binding protein-4 (LTBP4) is a multi-domain glycoprotein, essential for regulating the extracellular bioavailability of TGFβ and assembly of elastic fibre proteins, fibrillin-1 and tropoelastin. LTBP4 mutations are linked to autosomal recessive cutis laxa type 1C (ARCL1C), a rare congenital disease characterised by high mortality and severely disrupted connective tissues. Despite the importance of LTBP4, the structure and molecular consequences of disease mutations are unknown. Therefore, we analysed the structural and functional consequences of three ARCL1C causing point mutations which effect highly conserved cysteine residues. Our structural and biophysical data show that the LTBP4 N- and C-terminal regions are monomeric in solution and adopt extended conformations with the mutations resulting in subtle changes to their conformation. Similar to LTBP1, the N-terminal region is relatively inflexible, whereas the C-terminal region is flexible. Interaction studies show that one C-terminal mutation slightly decreases binding to fibrillin-1. We also found that the LTBP4 C-terminal region directly interacts with tropoelastin which is perturbed by both C-terminal ARCL1C mutations, whereas an N-terminal mutation increased binding to fibulin-4 but did not affect the interaction with heparan sulphate. Our results suggest that LTBP4 mutations contribute to ARCL1C by disrupting the structure and interactions of LTBP4 which are essential for elastogenesis in a range of mammalian connective tissues.

Subject Areas: Biology and Bio-materials

Instruments: B21-High Throughput SAXS

Other Facilities: BM29 at ESRF

Added On: 29/09/2021 11:44


Discipline Tags:

Life Sciences & Biotech Biophysics Genetics Health & Wellbeing Non-Communicable Diseases Structural biology

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)