The x-ray crystal structure of full-length human plasminogen

Ruby HP Law, Tom T Caradoc-Davies, Nathan P Cowieson, Anita J Horvath, Adam J Quek, Joana Amarante Da Encarnacao, David L Steer, Angus D Cowan, Qingwei Zhang, Bernadine GC Lu, Robert N Pike, Alexander Ian Smith, Paul B Coughlin, James C Whisstock

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Plasminogen is the proenzyme precursor of the primary fibrinolytic protease plasmin. Circulating plasminogen, which comprises a Pan-apple (PAp) domain, five kringle domains (KR1-5), and a serine protease (SP) domain, adopts a closed, activation-resistant conformation. The kringle domains mediate interactions with fibrin clots and cell-surface receptors. These interactions trigger plasminogen to adopt an open form that can be cleaved and converted to plasmin by tissue-type and urokinase-type plasminogen activators. Here, the structure of closed plasminogen reveals that the PAp and SP domains, together with chloride ions, maintain the closed conformation through interactions with the kringle array. Differences in glycosylation alter the position of KR3, although in all structures the loop cleaved by plasminogen activators is inaccessible. The ligand-binding site of KR1 is exposed and likely governs proenzyme recruitment to targets. Furthermore, analysis of our structure suggests that KR5 peeling away from the PAp domain may initiate plasminogen conformational change.
Original languageEnglish
Pages (from-to)185 - 190
Number of pages6
JournalCell Reports
Volume1
Issue number3
DOIs
Publication statusPublished - 2012

Cite this

Law, Ruby HP ; Caradoc-Davies, Tom T ; Cowieson, Nathan P ; Horvath, Anita J ; Quek, Adam J ; Amarante Da Encarnacao, Joana ; Steer, David L ; Cowan, Angus D ; Zhang, Qingwei ; Lu, Bernadine GC ; Pike, Robert N ; Smith, Alexander Ian ; Coughlin, Paul B ; Whisstock, James C. / The x-ray crystal structure of full-length human plasminogen. In: Cell Reports. 2012 ; Vol. 1, No. 3. pp. 185 - 190.
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title = "The x-ray crystal structure of full-length human plasminogen",
abstract = "Plasminogen is the proenzyme precursor of the primary fibrinolytic protease plasmin. Circulating plasminogen, which comprises a Pan-apple (PAp) domain, five kringle domains (KR1-5), and a serine protease (SP) domain, adopts a closed, activation-resistant conformation. The kringle domains mediate interactions with fibrin clots and cell-surface receptors. These interactions trigger plasminogen to adopt an open form that can be cleaved and converted to plasmin by tissue-type and urokinase-type plasminogen activators. Here, the structure of closed plasminogen reveals that the PAp and SP domains, together with chloride ions, maintain the closed conformation through interactions with the kringle array. Differences in glycosylation alter the position of KR3, although in all structures the loop cleaved by plasminogen activators is inaccessible. The ligand-binding site of KR1 is exposed and likely governs proenzyme recruitment to targets. Furthermore, analysis of our structure suggests that KR5 peeling away from the PAp domain may initiate plasminogen conformational change.",
author = "Law, {Ruby HP} and Caradoc-Davies, {Tom T} and Cowieson, {Nathan P} and Horvath, {Anita J} and Quek, {Adam J} and {Amarante Da Encarnacao}, Joana and Steer, {David L} and Cowan, {Angus D} and Qingwei Zhang and Lu, {Bernadine GC} and Pike, {Robert N} and Smith, {Alexander Ian} and Coughlin, {Paul B} and Whisstock, {James C}",
year = "2012",
doi = "10.1016/j.celrep.2012.02.012",
language = "English",
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journal = "Cell Reports",
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Law, RHP, Caradoc-Davies, TT, Cowieson, NP, Horvath, AJ, Quek, AJ, Amarante Da Encarnacao, J, Steer, DL, Cowan, AD, Zhang, Q, Lu, BGC, Pike, RN, Smith, AI, Coughlin, PB & Whisstock, JC 2012, 'The x-ray crystal structure of full-length human plasminogen' Cell Reports, vol. 1, no. 3, pp. 185 - 190. https://doi.org/10.1016/j.celrep.2012.02.012

The x-ray crystal structure of full-length human plasminogen. / Law, Ruby HP; Caradoc-Davies, Tom T; Cowieson, Nathan P; Horvath, Anita J; Quek, Adam J; Amarante Da Encarnacao, Joana; Steer, David L; Cowan, Angus D; Zhang, Qingwei; Lu, Bernadine GC; Pike, Robert N; Smith, Alexander Ian; Coughlin, Paul B; Whisstock, James C.

In: Cell Reports, Vol. 1, No. 3, 2012, p. 185 - 190.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The x-ray crystal structure of full-length human plasminogen

AU - Law, Ruby HP

AU - Caradoc-Davies, Tom T

AU - Cowieson, Nathan P

AU - Horvath, Anita J

AU - Quek, Adam J

AU - Amarante Da Encarnacao, Joana

AU - Steer, David L

AU - Cowan, Angus D

AU - Zhang, Qingwei

AU - Lu, Bernadine GC

AU - Pike, Robert N

AU - Smith, Alexander Ian

AU - Coughlin, Paul B

AU - Whisstock, James C

PY - 2012

Y1 - 2012

N2 - Plasminogen is the proenzyme precursor of the primary fibrinolytic protease plasmin. Circulating plasminogen, which comprises a Pan-apple (PAp) domain, five kringle domains (KR1-5), and a serine protease (SP) domain, adopts a closed, activation-resistant conformation. The kringle domains mediate interactions with fibrin clots and cell-surface receptors. These interactions trigger plasminogen to adopt an open form that can be cleaved and converted to plasmin by tissue-type and urokinase-type plasminogen activators. Here, the structure of closed plasminogen reveals that the PAp and SP domains, together with chloride ions, maintain the closed conformation through interactions with the kringle array. Differences in glycosylation alter the position of KR3, although in all structures the loop cleaved by plasminogen activators is inaccessible. The ligand-binding site of KR1 is exposed and likely governs proenzyme recruitment to targets. Furthermore, analysis of our structure suggests that KR5 peeling away from the PAp domain may initiate plasminogen conformational change.

AB - Plasminogen is the proenzyme precursor of the primary fibrinolytic protease plasmin. Circulating plasminogen, which comprises a Pan-apple (PAp) domain, five kringle domains (KR1-5), and a serine protease (SP) domain, adopts a closed, activation-resistant conformation. The kringle domains mediate interactions with fibrin clots and cell-surface receptors. These interactions trigger plasminogen to adopt an open form that can be cleaved and converted to plasmin by tissue-type and urokinase-type plasminogen activators. Here, the structure of closed plasminogen reveals that the PAp and SP domains, together with chloride ions, maintain the closed conformation through interactions with the kringle array. Differences in glycosylation alter the position of KR3, although in all structures the loop cleaved by plasminogen activators is inaccessible. The ligand-binding site of KR1 is exposed and likely governs proenzyme recruitment to targets. Furthermore, analysis of our structure suggests that KR5 peeling away from the PAp domain may initiate plasminogen conformational change.

UR - http://www.sciencedirect.com/science/article/pii/S2211124712000691

U2 - 10.1016/j.celrep.2012.02.012

DO - 10.1016/j.celrep.2012.02.012

M3 - Article

VL - 1

SP - 185

EP - 190

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 3

ER -