DOI: 10.1073/pnas.2334390100. Structure and functional significance of mechanically unfolded fibronectin type III <sub>1</sub> intermediates

Structure and functional significance of mechanically unfolded fibronectin type III 1 intermediates

10.1073/pnas.2334390100

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Fibronectin (FN) forms fibrillar networks coupling cells to the extracellular matrix. The formation of FN fibrils, fibrillogenesis, is a tightly regulated process involving the exposure of cryptic binding sites in individual FN type III (FN-III) repeats presumably exposed by mechanical tension. The FN-III 1 module has been previously proposed to contain such cryptic sites that promote the assembly of extracellular matrix FN fibrils. We have combined NMR and steered molecular dynamics simulations to study the structure and mechanical unfolding pathway of FN-III 1 . This study finds that FN-III 1 consists of a β-sandwich structure that unfolds to a mechanically stable intermediate about four times the length of the native folded state. Considering previous experimental findings, our studies provide a structural model by which mechanical stretching of FN-III 1 may induce fibrillogenesis through this partially unfolded intermediate.

Bibliography

Gao, M., Craig, D., Lequin, O., Campbell, I. D., Vogel, V., & Schulten, K. (2003). Structure and functional significance of mechanically unfolded fibronectin type III 1 intermediates. Proceedings of the National Academy of Sciences, 100(25), 14784â14789.

Authors 6

Mu Gao (first)
David Craig (additional)
Olivier Lequin (additional)
Iain D. Campbell (additional)
Viola Vogel (additional)
Klaus Schulten (additional)

References 40 Referenced 171

10.1038/35099066
10.1073/pnas.91.21.10114
10.1073/pnas.96.5.2153
10.1073/pnas.072650799
10.1073/pnas.251422998
10.1073/pnas.96.22.12518
10.1016/0092-8674(95)90184-1
10.1006/excr.1995.1069
10.1083/jcb.141.2.539
10.1016/S0021-9258(17)32292-5
10.1083/jcb.200112031
10.1083/jcb.200102034
10.1074/jbc.272.3.1718
10.1006/jmbi.1998.1863
10.1083/jcb.133.2.431
10.1074/jbc.273.5.2601
10.1038/367193a0
10.1083/jcb.118.2.421
10.1016/S0022-2836(03)00890-8
10.1073/pnas.98.2.620
10.1016/S0022-2836(02)00306-6
10.1016/S0959-440X(00)00194-9
10.1016/S0006-3495(98)77556-3
10.1038/47083
10.1074/jbc.M208956200
10.1006/jmre.1998.1361
10.1007/BF00227465
10.1006/jmbi.1997.1284
10.1016/S1090-7807(02)00014-9
10.1021/jp973084f
10.1073/pnas.96.4.1351
10.1006/jcph.1999.6201
10.1063/1.445869
Main, A. L., Harvey, T. S., Baron, M., Boyd, J. & Campbell, I. D. (1992) Cell 31, 671–678. / Cell (1992)
10.1016/S0092-8674(00)81002-8
10.1093/emboj/18.6.1468
10.1073/pnas.101582198
Craig D. Gao M. Schulten K. & Vogel V. (2004) Structure (Cambridge U.K.) in press.
10.1016/S0022-2836(02)01001-X
10.1016/0263-7855(96)00018-5

Dates

Type	When
Created	21 years, 8 months ago (Dec. 9, 2003, 1:17 p.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 9:30 a.m.)
Indexed	1 month ago (July 30, 2025, 11:24 a.m.)
Issued	21 years, 9 months ago (Dec. 1, 2003)
Published	21 years, 9 months ago (Dec. 1, 2003)
Published Online	21 years, 9 months ago (Dec. 1, 2003)
Published Print	21 years, 8 months ago (Dec. 9, 2003)

Funders 0

None

BibTeX

@article{Gao_2003, title={Structure and functional significance of mechanically unfolded fibronectin type III 1 intermediates}, volume={100}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.2334390100}, DOI={10.1073/pnas.2334390100}, number={25}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Gao, Mu and Craig, David and Lequin, Olivier and Campbell, Iain D. and Vogel, Viola and Schulten, Klaus}, year={2003}, month=dec, pages={14784–14789} }

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