The compact and biologically relevant structure of inter-α-inhibitor is maintained by the chondroitin sulfate chain and divalent cations

Carsten Scavenius; Camilla Lund Nikolajsen; Marcel Stenvang; Ida Thøgersen; Lukasz Wyrozemski; Hans-Georg Wisniewski; Daniel E Otzen; Kristian W Sanggaard; Jan J Enghild

doi:10.1074/jbc.M115.678748

The compact and biologically relevant structure of inter-α-inhibitor is maintained by the chondroitin sulfate chain and divalent cations

Carsten Scavenius, Camilla Lund Nikolajsen, Marcel Stenvang, Ida Thøgersen, Lukasz Wyrozemski, Hans-Georg Wisniewski, Daniel E Otzen, Kristian W Sanggaard, Jan J Enghild

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

6 Citations (Scopus)

Abstract

Inter-α-inhibitor is a proteoglycan of unique structure. The protein consists of three subunits, heavy chain 1, heavy chain 2, and bikunin covalently joined by a chondroitin sulfate chain originating at Ser-10 of bikunin. Inter-α-inhibitor interacts with an inflammation-associated protein, tumor necrosis factor- inducible gene 6 protein, in the extracellular matrix. This interaction leads to transfer of the heavy chains from the chondroitin sulfate of inter-α-inhibitor to hyaluronan and consequently to matrix stabilization. Divalent cations and heavy chain 2 are essential co-factors in this transfer reaction. In the present study, we have investigated how divalent cations in concert with the chondroitin sulfate chain influence the structure and stability of inter- α -inhibitor. The results showed that Mg ²⁺ or Mn ²⁺, but not Ca ²⁺, induced a conformational change in inter-α-inhibitor as evidenced by a decrease in the Stokes radius and a bikunin chondroitin sulfate-dependent increase of the thermodynamic stability. This structure was shown to be essential for the ability of inter-α-inhibitor to participate in extracellular matrix stabilization. In addition, the data revealed that bikunin was positioned adjacent to both heavy chains and that the two heavy chains also were in close proximity. The chondroitin sulfate chain interacted with all protein components and inter- α - inhibitor dissociated when it was degraded. Conventional purification protocols result in the removal of the Mg ²⁺ found in plasma and because divalent cations influence the conformation and affect function it is important to consider this when characterizing the biological activity of inter- α -inhibitor.

Original language	English
Journal	Journal of Biological Chemistry
Volume	291
Issue	9
Pages (from-to)	4658-4670
Number of pages	13
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.M115.678748
Publication status	Published - 26 Feb 2016

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Scavenius, C., Nikolajsen, C. L., Stenvang, M., Thøgersen, I., Wyrozemski, L., Wisniewski, H.-G., Otzen, D. E., Sanggaard, K. W., & Enghild, J. J. (2016). The compact and biologically relevant structure of inter-α-inhibitor is maintained by the chondroitin sulfate chain and divalent cations. Journal of Biological Chemistry, 291(9), 4658-4670. https://doi.org/10.1074/jbc.M115.678748

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title = "The compact and biologically relevant structure of inter-α-inhibitor is maintained by the chondroitin sulfate chain and divalent cations",

abstract = "Inter-α-inhibitor is a proteoglycan of unique structure. The protein consists of three subunits, heavy chain 1, heavy chain 2, and bikunin covalently joined by a chondroitin sulfate chain originating at Ser-10 of bikunin. Inter-α-inhibitor interacts with an inflammation-associated protein, tumor necrosis factor- inducible gene 6 protein, in the extracellular matrix. This interaction leads to transfer of the heavy chains from the chondroitin sulfate of inter-α-inhibitor to hyaluronan and consequently to matrix stabilization. Divalent cations and heavy chain 2 are essential co-factors in this transfer reaction. In the present study, we have investigated how divalent cations in concert with the chondroitin sulfate chain influence the structure and stability of inter- α -inhibitor. The results showed that Mg 2+ or Mn 2+, but not Ca 2+, induced a conformational change in inter-α-inhibitor as evidenced by a decrease in the Stokes radius and a bikunin chondroitin sulfate-dependent increase of the thermodynamic stability. This structure was shown to be essential for the ability of inter-α-inhibitor to participate in extracellular matrix stabilization. In addition, the data revealed that bikunin was positioned adjacent to both heavy chains and that the two heavy chains also were in close proximity. The chondroitin sulfate chain interacted with all protein components and inter- α - inhibitor dissociated when it was degraded. Conventional purification protocols result in the removal of the Mg 2+ found in plasma and because divalent cations influence the conformation and affect function it is important to consider this when characterizing the biological activity of inter- α -inhibitor.",

author = "Carsten Scavenius and Nikolajsen, {Camilla Lund} and Marcel Stenvang and Ida Th{\o}gersen and Lukasz Wyrozemski and Hans-Georg Wisniewski and Otzen, {Daniel E} and Sanggaard, {Kristian W} and Enghild, {Jan J}",

note = "Copyright {\textcopyright} 2016, The American Society for Biochemistry and Molecular Biology.",

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day = "26",

doi = "10.1074/jbc.M115.678748",

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Scavenius, C, Nikolajsen, CL, Stenvang, M, Thøgersen, I, Wyrozemski, L, Wisniewski, H-G, Otzen, DE, Sanggaard, KW & Enghild, JJ 2016, 'The compact and biologically relevant structure of inter-α-inhibitor is maintained by the chondroitin sulfate chain and divalent cations', Journal of Biological Chemistry, vol. 291, no. 9, pp. 4658-4670. https://doi.org/10.1074/jbc.M115.678748

The compact and biologically relevant structure of inter-α-inhibitor is maintained by the chondroitin sulfate chain and divalent cations. / Scavenius, Carsten; Nikolajsen, Camilla Lund; Stenvang, Marcel et al.
In: Journal of Biological Chemistry, Vol. 291, No. 9, 26.02.2016, p. 4658-4670.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - The compact and biologically relevant structure of inter-α-inhibitor is maintained by the chondroitin sulfate chain and divalent cations

AU - Scavenius, Carsten

AU - Nikolajsen, Camilla Lund

AU - Stenvang, Marcel

AU - Thøgersen, Ida

AU - Wyrozemski, Lukasz

AU - Wisniewski, Hans-Georg

AU - Otzen, Daniel E

AU - Sanggaard, Kristian W

AU - Enghild, Jan J

PY - 2016/2/26

Y1 - 2016/2/26

N2 - Inter-α-inhibitor is a proteoglycan of unique structure. The protein consists of three subunits, heavy chain 1, heavy chain 2, and bikunin covalently joined by a chondroitin sulfate chain originating at Ser-10 of bikunin. Inter-α-inhibitor interacts with an inflammation-associated protein, tumor necrosis factor- inducible gene 6 protein, in the extracellular matrix. This interaction leads to transfer of the heavy chains from the chondroitin sulfate of inter-α-inhibitor to hyaluronan and consequently to matrix stabilization. Divalent cations and heavy chain 2 are essential co-factors in this transfer reaction. In the present study, we have investigated how divalent cations in concert with the chondroitin sulfate chain influence the structure and stability of inter- α -inhibitor. The results showed that Mg 2+ or Mn 2+, but not Ca 2+, induced a conformational change in inter-α-inhibitor as evidenced by a decrease in the Stokes radius and a bikunin chondroitin sulfate-dependent increase of the thermodynamic stability. This structure was shown to be essential for the ability of inter-α-inhibitor to participate in extracellular matrix stabilization. In addition, the data revealed that bikunin was positioned adjacent to both heavy chains and that the two heavy chains also were in close proximity. The chondroitin sulfate chain interacted with all protein components and inter- α - inhibitor dissociated when it was degraded. Conventional purification protocols result in the removal of the Mg 2+ found in plasma and because divalent cations influence the conformation and affect function it is important to consider this when characterizing the biological activity of inter- α -inhibitor.

AB - Inter-α-inhibitor is a proteoglycan of unique structure. The protein consists of three subunits, heavy chain 1, heavy chain 2, and bikunin covalently joined by a chondroitin sulfate chain originating at Ser-10 of bikunin. Inter-α-inhibitor interacts with an inflammation-associated protein, tumor necrosis factor- inducible gene 6 protein, in the extracellular matrix. This interaction leads to transfer of the heavy chains from the chondroitin sulfate of inter-α-inhibitor to hyaluronan and consequently to matrix stabilization. Divalent cations and heavy chain 2 are essential co-factors in this transfer reaction. In the present study, we have investigated how divalent cations in concert with the chondroitin sulfate chain influence the structure and stability of inter- α -inhibitor. The results showed that Mg 2+ or Mn 2+, but not Ca 2+, induced a conformational change in inter-α-inhibitor as evidenced by a decrease in the Stokes radius and a bikunin chondroitin sulfate-dependent increase of the thermodynamic stability. This structure was shown to be essential for the ability of inter-α-inhibitor to participate in extracellular matrix stabilization. In addition, the data revealed that bikunin was positioned adjacent to both heavy chains and that the two heavy chains also were in close proximity. The chondroitin sulfate chain interacted with all protein components and inter- α - inhibitor dissociated when it was degraded. Conventional purification protocols result in the removal of the Mg 2+ found in plasma and because divalent cations influence the conformation and affect function it is important to consider this when characterizing the biological activity of inter- α -inhibitor.

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U2 - 10.1074/jbc.M115.678748

DO - 10.1074/jbc.M115.678748

M3 - Journal article

C2 - 26728454

SN - 0021-9258

VL - 291

SP - 4658

EP - 4670

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 9

ER -

The compact and biologically relevant structure of inter-α-inhibitor is maintained by the chondroitin sulfate chain and divalent cations

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