The domain within your query sequence starts at position 23 and ends at position 103; the E-value for the KR domain shown below is 3.64e-17.

GGCFWDNGHLYREDQPSPAPGLRCLNWLAAQGSRESLTEPSPGNHNYCRNPDQDPRGPWC
YISSETGVPEKRPCEDVSCPE

KR

Kringle domain

• SMART accession number: SM00130
• Description: Named after a Danish pastry. Found in several serine proteases and in ROR-like receptors. Can occur in up to 38 copies (in apolipoprotein(a)). Plasminogen-like kringles possess affinity for free lysine and lysine- containing peptides.
• Interpro abstract (IPR000001):

  Kringles are autonomous structural domains, found throughout the blood clotting and fibrinolytic proteins. Kringle domains are believed to play a role in binding mediators (e.g., membranes, other proteins or phospholipids), and in the regulation of proteolytic activity [ (PUBMED:3886654) (PUBMED:6373375) (PUBMED:2157850) ]. Kringle domains [ (PUBMED:3131537) (PUBMED:3891096) (PUBMED:1879523) ] are characterised by a triple loop, 3-disulphide bridge structure, whose conformation is defined by a number of hydrogen bonds and small pieces of anti-parallel beta-sheet. They are found in a varying number of copies in some plasma proteins including prothrombin and urokinase-type plasminogen activator, which are serine proteases belonging to MEROPS peptidase family S1A.

There are 13009 KR domains in 7555 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Castellino FJ, McCance SG
• The kringle domains of human plasminogen.
• Ciba Found Symp. 1997; 212: 46-60

The mature form of the zymogen, human plasminogen (HPlg), contains 791 amino acids present in a single polypeptide chain. The fibrinolytic enzyme, human plasmin (HPlm), is formed from HPlg as a result of activator-catalysed cleavage of the Arg561-Val562 peptide bond in HPlg. The resulting HPlm contains a heavy chain of 561 amino acid residues, originating from the N-terminus of HPlg, doubly disulfide-linked to a light chain of 230 amino acid residues. This latter region, containing the C-terminus of HPlg, is homologous to serine proteases such as trypsin and elastase. The heavy chain of HPlm consists of five repeating triple-disulfide-linked peptide regions, c. 80 amino acid residues in length, termed kringles (K), that are responsible for interactions of HPlg and HPlm with substrates, inhibitors and regulators of HPlg activation. Important among the ligands of the kringles are positive activation effectors, typified by lysine and its analogues, and negative activation effectors, such as Cl-. The kringle domains of HPlg that participate in these binding interactions are K1, K4 and K5, and perhaps K2. These modules appear to function as independent domains. The amino acid residues important in these kringle/ligand binding interactions have been proposed by structural determinations, and their relative importance quantified by site-directed mutagenesis experimentation.

• Gherardi E, GonzalezManzano R, Cottage A, Hawker K, Aparicio S
• Evolution of plasminogen-related growth factors (HGF/SF and HGF1/MSP).
• Ciba Found Symp. 1997; 212: 24-35

HGF/SF and HGF1/MSP define a novel growth factor family whose members share the domain structure and the proteolytic process of activation of the blood proteinase precursor plasminogen. The amino acid and RNA sequences of HGF/SF and HGF1/MSP, the intron-exon organization of their genes and the predicted 3D structure of individual domains indicate that HGF/SF and HGF1/MSP evolved along with plasminogen and other members of the kringle-serine proteinase (KSP) superfamily from an ancestral gene that contained a single copy of the kringle domain, a serine proteinase domain and an activation peptide connecting the two domains. A series of intragenic duplications of the kringle domain, gene duplications, exon shuffling and deletions is responsible for the genes currently present in mammals, avians and amphibians. Plasminogen, HGF/SF and HGF1/MSP represent paradigmatic examples of the modern, multi-domain proteins typically associated with vertebrate organisms and illustrate a novel evolutionary pathway that led to the emergence of molecules with growth regulatory activity from proteolytic enzymes.

• Harlos K, Boys CW, Holland SK, Esnouf MP, Blake CC
• Structure and order of the protein and carbohydrate domains of prothrombin fragment 1.
• FEBS Lett. 1987; 224: 97-103

The three-dimensional structure of prothrombin fragment 1 has been determined by X-ray crystallography at 3.8 A resolution. The fragment is composed of a number of structural units, some of which are ordered while others are disordered. The ordered part of the structure includes a compact kringle unit, a helical domain and a carbohydrate chain. The kringle structure is organized around a close pair of buried disulfide bridges. One of its carbohydrate chains, that attached to Asn 101, is fully ordered, but the carbohydrate chain attached to Asn 77 appears to be disordered. The calcium binding unit is composed of a disordered part containing all ten gamma-carboxyglutamic acid residues and an ordered part forming the helical domain. The highly conserved residues Phe 41, Trp 42 and Tyr 45, which form a hydrophobic cluster on the first helix, interact around a crystallographic two-fold axis with the equivalent residues in another molecule to form a dimer in the crystal.

• Park CH, Tulinsky A
• Three-dimensional structure of the kringle sequence: structure of prothrombin fragment 1.
• Biochemistry. 1986; 25: 3977-82

The three-dimensional structure of bovine prothrombin fragment 1 has been solved at 2.8-A resolution. The electron density clearly reveals four disulfide bridges along with more than 80% of the side chains completely in density, which correspond faithfully to the kringle sequence, its preceding 30 residues, and the dodecapeptide carboxy terminal; the polysaccharide and the first 35 residues of the amino terminal of fragment 1 are disordered or about 40% of the structure. The folding of the kringle sequence is based upon close disulfide van der Waals contacts between Cys-87-Cys-127 and Cys-115-Cys-139 (4.1 A between midpoints of the bridges), two antiparallel strands of highly conserved (113-118, 124-129) beta-structure, and the stacking of some conserved aromatic residues, all near the center of the folded structure. Moreover, the overall folding appears to be duplicated as a pair of stacked duplex loops with an antiparallel open loop. The overall shape of the kringle structure approximates an eccentric oblate ellipsoid of dimensions 11 X 28 X 30 A. The residues immediately preceding the kringle are dominated by alpha-helical structure (Phe-41-Cys-48; Leu-56-Glu-63). Residues Phe-41-Trp-42 and Tyr-45, which are conserved in factor IX, factor X, protein C, and protein Z, form another aromatic stacked cluster while the Cys-48-Cys-61 disulfide loop corresponds to the well-known alpha/beta structural unit. The dodecapeptide carboxy-terminal interkringle chain extends along the periphery of the kringle in its plane and forms a beta-structure with the kringle-closing Ser-140-Val-143 tetrapeptide.

• Sottrup-Jensen L, Zajdel M, Claeys H, Petersen TE, Magnusson S
• Amino-acid sequence of activation cleavage site in plasminogen: homology with "pro" part of prothrombin.
• Proc Natl Acad Sci U S A. 1975; 72: 2577-81

A 38-residue fragment is isolated from carboxymethylated plasminogen. Residues 29-38 have the same sequence as the amino-terminal end of the light chain of plasmin. The sequence 1-28 is therefore the sequence of the carboxyl-terminal end of the heavy chain and contains the specific sequence at which urokinase (EC 3.4.99.26) and other plasminogen-activating serine proteases split. Two of the five carboxymethyl-cysteine residues in the isolated fragment are situated close to the cleavage site and the fragment is not itself a substrate for plasminogen-activators. Residues 1-11 show extensive sequence homology with residues 137-147 and 242-252 in prothrombin, which are located in corresponding regions of the two internally homologous 83-residue structures in the non-thrombin part of the molecule, indicating that such structures may be a common feature of the non-protease part of the larger serine protease zymogens.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the KR domain.

Protein	Disease
Apolipoprotein(a) (P08519) (SMART)	OMIM:152200: {Coronary artery disease, susceptibility to}

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
39.80	map04610	Complement and coagulation cascades
18.37	map04080	Neuroactive ligand-receptor interaction
9.18	map04810	Regulation of actin cytoskeleton
8.16	map04060	Cytokine-cytokine receptor interaction
8.16	map04510	Focal adhesion
8.16	map05211	Renal cell carcinoma
8.16	map05218	Melanoma

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with KR domain which could be assigned to a KEGG orthologous group, and not all proteins containing KR domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of KR domains in PDB

PDB code	Title
1a0h	THE X-RAY CRYSTAL STRUCTURE OF PPACK-MEIZOTHROMBIN DESF1: KRINGLE/THROMBIN AND CARBOHYDRATE/KRINGLE/THROMBIN INTERACTIONS AND LOCATION OF THE LINKER CHAIN
1b2i	KRINGLE 2 DOMAIN OF HUMAN PLASMINOGEN: NMR SOLUTION STRUCTURE OF TRANS-4-AMINOMETHYLCYCLOHEXANE-1-CARBOXYLIC ACID (AMCHA) COMPLEX
1bht	NK1 FRAGMENT OF HUMAN HEPATOCYTE GROWTH FACTOR
1cea	THE STRUCTURE OF THE NON-COVALENT COMPLEX OF RECOMBINANT KRINGLE 1 DOMAIN OF HUMAN PLASMINOGEN WITH EACA (EPSILON-AMINOCAPROIC ACID)
1ceb	THE STRUCTURE OF THE NON-COVALENT COMPLEX OF RECOMBINANT KRINGLE 1 DOMAIN OF HUMAN PLASMINOGEN WITH AMCHA (TRANS-4-AMINOMETHYLCYCLOHEXANE-1-CARBOXYLIC ACID)
1gmn	Crystal structures of NK1-heparin complexes reveal the basis for NK1 activity and enable engineering of potent agonists of the MET receptor
1gmo	Crystal structures of NK1-heparin complexes reveal the basis for NK1 activity and enable engineering of potent agonists of the MET receptor
1gp9	A NEW CRYSTAL FORM OF THE NK1 SPLICE VARIANT OF HGF/SF DEMONSTRATES EXTENSIVE HINGE MOVEMENT AND SUGGESTS THAT THE NK1 DIMER ORIGINATES BY DOMAIN SWAPPING
1hpj	SOLUTION NMR STRUCTURE OF THE HUMAN PLASMINOGEN KRINGLE 1 DOMAIN COMPLEXED WITH 6-AMINOHEXANOIC ACID AT PH 5.3, 310K, DERIVED FROM RANDOMLY GENERATED STRUCTURES USING SIMULATED ANNEALING, 12 STRUCTURES
1hpk	SOLUTION NMR STRUCTURE OF THE HUMAN PLASMINOGEN KRINGLE 1 DOMAIN COMPLEXED WITH 6-AMINOHEXANOIC ACID AT PH 5.3, 310K, DERIVED FROM RANDOMLY GENERATED STRUCTURES USING SIMULATED ANNEALING, MINIMIZED AVERAGE STRUCTURE
1i5k	STRUCTURE AND BINDING DETERMINANTS OF THE RECOMBINANT KRINGLE-2 DOMAIN OF HUMAN PLASMINOGEN TO AN INTERNAL PEPTIDE FROM A GROUP A STREPTOCOCCAL SURFACE PROTEIN
1i71	HIGH RESOLUTION CRYSTAL STRUCTURE OF APOLIPOPROTEIN(A) KRINGLE IV TYPE 7: INSIGHTS INTO LIGAND BINDING
1jfn	SOLUTION STRUCTURE OF HUMAN APOLIPOPROTEIN(A) KRINGLE IV TYPE 6
1kdu	SEQUENTIAL 1H NMR ASSIGNMENTS AND SECONDARY STRUCTURE OF THE KRINGLE DOMAIN FROM UROKINASE
1ki0	The X-ray Structure of Human Angiostatin
1kiv	RECOMBINANT KRINGLE IV-10/M66 VARIANT OF HUMAN APOLIPOPROTEIN(A)
1krn	STRUCTURE OF KRINGLE 4 AT 4C TEMPERATURE AND 1.67 ANGSTROMS RESOLUTION
1nk1	NK1 FRAGMENT OF HUMAN HEPATOCYTE GROWTH FACTOR/SCATTER FACTOR (HGF/SF) AT 2.5 ANGSTROM RESOLUTION
1nl1	BOVINE PROTHROMBIN FRAGMENT 1 IN COMPLEX WITH CALCIUM ION
1nl2	BOVINE PROTHROMBIN FRAGMENT 1 IN COMPLEX WITH CALCIUM AND LYSOPHOSPHOTIDYLSERINE
1pk2	SOLUTION STRUCTURE OF THE TISSUE-TYPE PLASMINOGEN ACTIVATOR KRINGLE 2 DOMAIN COMPLEXED TO 6-AMINOHEXANOIC ACID AN ANTIFIBRINOLYTIC DRUG
1pk4	CRYSTAL AND MOLECULAR STRUCTURE OF HUMAN PLASMINOGEN KRINGLE 4 REFINED AT 1.9-ANGSTROMS RESOLUTION
1pkr	THE STRUCTURE OF RECOMBINANT PLASMINOGEN KRINGLE 1 AND THE FIBRIN BINDING SITE
1pmk	KRINGLE-KRINGLE INTERACTIONS IN MULTIMER KRINGLE STRUCTURES
1pml	KRINGLE-KRINGLE INTERACTIONS IN MULTIMER KRINGLE STRUCTURES
1tpk	CRYSTAL STRUCTURE OF THE KRINGLE-2 DOMAIN OF TISSUE PLASMINOGEN ACTIVATOR AT 2.4-ANGSTROMS RESOLUTION
1urk	SOLUTION STRUCTURE OF THE AMINO TERMINAL FRAGMENT OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR
2doh	The X-ray crystallographic structure of the angiogenesis inhibitor, angiostatin, bound a to a peptide from the group A streptococcal surface protein PAM
2doi	The X-ray crystallographic structure of the angiogenesis inhibitor, angiostatin, bound to a peptide from the group A streptococcus protein PAM
2fd6	Structure of Human Urokinase Plasminogen Activator in Complex with Urokinase Receptor and an anti-upar antibody at 1.9 A
2feb	NMR Solution Structure, Dynamics and Binding Properties of the Kringle IV Type 8 module of apolipoprotein(a)
2hpp	STRUCTURES OF THE NONCOVALENT COMPLEXES OF HUMAN AND BOVINE PROTHROMBIN FRAGMENT 2 WITH HUMAN PPACK-THROMBIN
2hpq	STRUCTURES OF THE NONCOVALENT COMPLEXES OF HUMAN AND BOVINE PROTHROMBIN FRAGMENT 2 WITH HUMAN PPACK-THROMBIN
2i9a	Crystal structure of the free aminoterminal fragment of urokinase type plasminogen activator (ATF)
2i9b	Crystal structure of ATF-urokinase receptor complex
2k4r	NMR solution structure of the neurotrypsin kringle domain
2k51	NMR Solution Structure of the Neurotrypsin Kringle Domain
2kj4	Solution structure of the complex of VEK-30 and plasminogen kringle 2
2knf	Solution structure and functional characterization of human plasminogen kringle 5
2l0s	Solution Structure of Human Plasminogen Kringle 3
2pf1	STRUCTURE OF BOVINE PROTHROMBIN FRAGMENT 1 REFINED AT 2.25 ANGSTROMS RESOLUTION
2pf2	THE CA+2 ION AND MEMBRANE BINDING STRUCTURE OF THE GLA DOMAIN OF CA-PROTHROMBIN FRAGMENT 1
2pk4	THE REFINED STRUCTURE OF THE EPSILON-AMINOCAPROIC ACID COMPLEX OF HUMAN PLASMINOGEN KRINGLE
2qj2	A Mechanistic Basis for Converting a Receptor Tyrosine Kinase Agonist to an Antagonist
2qj4	A Mechanistic Basis for Converting a Receptor Tyrosine Kinase Agonist to an Antagonist
2spt	DIFFERENCES IN THE METAL ION STRUCTURE BETWEEN SR-AND CA-PROTHROMBIN FRAGMENT 1
3bt1	Structure of urokinase receptor, urokinase and vitronectin complex
3bt2	Structure of urokinase receptor, urokinase and vitronectin complex
3e6p	Crystal structure of human meizothrombin desF1
3hn4	Crystal structure of the NK2 fragment (28-289) of human hepatocyte growth factor/scatter factor
3k65	Crystal Structure of Prethombin-2/Fragment-2 Complex
3kiv	RECOMBINANT KRINGLE IV-10/M66 VARIANT OF HUMAN APOLIPOPROTEIN(A)
3laq	Structure-based engineering of species selectivity in the uPA-uPAR interaction
3mkp	Crystal structure of 1K1 mutant of Hepatocyte Growth Factor/Scatter Factor fragment NK1 in complex with heparin
3nxp	Crystal structure of human prethrombin-1
3sp8	Crystal structure of NK2 in complex with fractionated Heparin DP10
3u73	Crystal structure of stabilized human uPAR mutant in complex with ATF
4a5t	STRUCTURAL BASIS FOR THE CONFORMATIONAL MODULATION
4bv5	4BV5
4bv7	4BV7
4bvc	4BVC
4bvd	4BVD
4bvv	4BVV
4bvw	4BVW
4cik	4CIK
4d3c	4D3C
4dur	The X-ray Crystal Structure of Full-Length type II Human Plasminogen
4duu	The X-ray Crystal Structure of Full-Length type I Human Plasminogen
4hzh	Structure of recombinant Gla-domainless prothrombin mutant S525A
4iua	Crystal Structure of the NK2 Fragment (31-290) of the mouse Hepatocyte Growth Factor/Scatter Factor
4k24	Structure of anti-uPAR Fab ATN-658 in complex with uPAR
4kiv	RECOMBINANT KRINGLE IV-10/W72R MUTANT OF HUMAN APOLIPOPROTEIN(A)
4nzq	Crystal structure of Ca2+-free prothrombin deletion mutant residues 146-167
4o03	Crystal structure of Ca2+ bound prothrombin deletion mutant residues 146-167
5coe	5COE
5cp9	5CP9
5cs1	5CS1
5cs3	5CS3
5cs5	5CS5
5cs9	5CS9
5csq	5CSQ
5ct1	5CT1
5ct2	5CT2
5ct3	5CT3
5edk	5EDK
5edm	5EDM
5fws	5FWS
5fwt	5FWT
5fwu	5FWU
5fwv	5FWV
5fww	5FWW
5hpg	STRUCTURE AND LIGAND DETERMINANTS OF THE RECOMBINANT KRINGLE 5 DOMAIN OF HUMAN PLASMINOGEN

Links (links to other resources describing this domain)

• PFAM: kringle
• INTERPRO: IPR000001
• PROSITE: KR_DOMAIN