DOI: 10.1073/pnas.111150598. Corneal collagen fibril structure in three dimensions: Structural insights into fibril assembly, mechanical properties, and tissue organization

Corneal collagen fibril structure in three dimensions: Structural insights into fibril assembly, mechanical properties, and tissue organization

10.1073/pnas.111150598

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The ability of the cornea to transmit light while being mechanically resilient is directly attributable to the formation of an extracellular matrix containing orthogonal sheets of collagen fibrils. The detailed structure of the fibrils and how this structure underpins the mechanical properties and organization of the cornea is understood poorly. In this study, we used automated electron tomography to study the three-dimensional organization of molecules in corneal collagen fibrils. The reconstructions show that the collagen molecules in the 36-nm diameter collagen fibrils are organized into microfibrils (≈4-nm diameter) that are tilted by ≈15° to the fibril long axis in a right-handed helix. An unexpected finding was that the microfibrils exhibit a constant-tilt angle independent of radial position within the fibril. This feature suggests that microfibrils in concentric layers are not always parallel to each other and cannot retain the same neighbors between layers. Analysis of the lateral structure shows that the microfibrils exhibit regions of order and disorder within the 67-nm axial repeat of collagen fibrils. Furthermore, the microfibrils are ordered at three specific regions of the axial repeat of collagen fibrils that correspond to the N- and C-telopeptides and the d-band of the gap zone. The reconstructions also show macromolecules binding to the fibril surface at sites that correspond precisely to where the microfibrils are most orderly.

Bibliography

Holmes, D. F., Gilpin, C. J., Baldock, C., Ziese, U., Koster, A. J., & Kadler, K. E. (2001). Corneal collagen fibril structure in three dimensions: Structural insights into fibril assembly, mechanical properties, and tissue organization. Proceedings of the National Academy of Sciences, 98(13), 7307â7312.

Authors 6

David F. Holmes (first)
Christopher J. Gilpin (additional)
Clair Baldock (additional)
Ulrike Ziese (additional)
Abraham J. Koster (additional)
Karl E. Kadler (additional)

References 43 Referenced 200

10.1006/jsbi.1998.3991
10.1016/0022-2836(84)90424-8
10.1038/282878a0
10.1016/0022-2836(87)90631-0
10.1016/0141-8130(81)90018-0
10.1038/219157a0
10.1016/0022-2836(78)90419-9
10.1007/BF01114803
10.1006/jmbi.1997.1449
10.1083/jcb.106.3.999
10.1042/bj3160001
10.1006/dbio.1999.9383
10.1016/S0021-9258(18)47783-6
10.1083/jcb.121.5.1181
10.1016/S0968-4328(00)00043-3
10.1016/S0021-9258(19)77922-8
10.1083/jcb.106.3.991
Holden P. Meadows R. S. Chapman K. L. Grant M. E. Kadler K. E. & Briggs M. D. (2001) J. Biol. Chem. in press.
Thur J. Rosenberg K. Nitsche D. P. Pihlajamaa T. Ala-Kokko L. Heinegard D. Paulsson M. & Maurer P. (2001) J. Biol. Chem. in press.
10.1073/pnas.84.17.6040
10.1002/(SICI)1097-0177(199605)206:1<49::AID-AJA5>3.0.CO;2-0
10.1096/fasebj.10.5.8621059
10.1074/jbc.274.27.18843
10.1006/exer.1999.0789
10.1083/jcb.141.5.1277
10.1038/75664
10.1006/jmbi.1999.3384
10.1006/jsbi.1996.0013
10.1016/0889-1605(86)90018-2
10.1016/0022-2836(82)90317-5
10.1016/0892-0354(90)90018-N
10.1016/0141-8130(89)90009-3
10.1111/j.1432-1033.1994.00943.x
10.1074/jbc.270.32.18865
10.1016/0005-2795(70)90303-X
10.1002/bip.360211115
10.1074/jbc.273.25.15598
10.1042/bj2520313
S Chakravarti, M Petroll, J Hassell, J Jester, J H Lass, J Paul, D E Birk Invest Ophthalmol Visual Sci 41, 3365–3373 (2000). / Invest Ophthalmol Visual Sci by Chakravarti S (2000)
10.1074/jbc.C000278200
Y Lan, C Cummings, J K Sheehan, K E Kadler, D F Holmes, J A Chapman Dermatan Sulphate Proteoglycans. Chemistry, Biology, Chemical Pathology, ed J E Scott (Portland Press, London), pp. 183–192 (1993). / Dermatan Sulphate Proteoglycans. Chemistry, Biology, Chemical Pathology by Lan Y (1993)
10.1159/000055616
10.1016/0892-0354(90)90018-N

Dates

Type	When
Created	23 years ago (July 26, 2002, 10:37 a.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 8:46 p.m.)
Indexed	2 weeks, 2 days ago (Aug. 6, 2025, 9:27 a.m.)
Issued	24 years, 2 months ago (June 5, 2001)
Published	24 years, 2 months ago (June 5, 2001)
Published Online	24 years, 2 months ago (June 5, 2001)
Published Print	24 years, 2 months ago (June 19, 2001)

Funders 0

None

BibTeX

@article{Holmes_2001, title={Corneal collagen fibril structure in three dimensions: Structural insights into fibril assembly, mechanical properties, and tissue organization}, volume={98}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.111150598}, DOI={10.1073/pnas.111150598}, number={13}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Holmes, David F. and Gilpin, Christopher J. and Baldock, Clair and Ziese, Ulrike and Koster, Abraham J. and Kadler, Karl E.}, year={2001}, month=jun, pages={7307–7312} }

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