Cystatin S: A Cysteine Proteinase Inhibitor of Human Saliva

Isemura, Satoko; Saitoh, Eiichi; Ito, Seiki; Isemura, Mamoru; Sanada, Kazuo

doi:10.1093/oxfordjournals.jbchem.a134952

Cited by 115 publications

(63 citation statements)

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“…(30). It has been suggested that the active site of the cysteine proteinase inhibitors may be located between positions 53 and 69 because this segment is the most conserved region in all known cystatins (19,33,(35)(36)(37). Moreover, human kininogens, which inhibit papain and cathepsin L (38), have a duplicated segment homologous to positions 53-69 and are codified by discontinuous DNA segments (39) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C).

Ghiso¹,

Jensson²,

Frangione³

1986

Proc. Natl. Acad. Sci. U.S.A.

282

142

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A -trace variant protein is the major constituent of the amyloid fibrils in patients from Iceland with hereditary cerebral hemorrhage with amyloidosis. The protein consists of 110 residues and is similar to human urinary V-trace basic protein (or cystatin C) beginning at its 11th aminoterminal residue. It has an amino acid substitution (glutamine for leucine) at position 58 (position 68 in v-trace numbering), which is near the proposed active site of related proteinsnamely, cysteine protease inhibitors and kininogens. It is postulated that a point mutation has occurred, leading to the production of an unusual protein that is abnormally degraded, bound, and/or precipitated. Alternatively, Vtrace basic protein may be genetically polymorphic, and the variant described here may represent an as-yet-undiscovered isotype or an allelic form that is linked to, but not responsible for, the deposition disease. Our data on the structure of a V-trace variant protein suggests that its gene expresses a polyprotein precursor in which active peptides are flanked by basic amino acid residues that permit cleavage to liberate small internal peptides. It is likely that the nucleotide sequence coding for Arg-Xaa and Lys-Xaa repeated several times in the molecule may function as alternative splicing sites for mRNA processing.Amyloidosis comprises a heterogeneous group of disorders of different etiology characterized by the relentless deposition (mainly extracellular) of a number of fibrillar proteins, which may be distinguished from each other immunohistologically and biochemically. Amyloid fibrils are composed of low molecular weight subunits that originate by polymerization and/or proteolysis of serum proteins. These subunit proteins have a predominant 3-pleated-sheet configuration, as shown by spectroscopic studies and x-ray diffraction (1).Hereditary cerebral hemorrhage with amyloidosis (HCH-WA) is an autosomal dominant form of amyloidosis that is restricted to the cerebral vasculature and leads to hemorrhagic and thrombotic strokes causing death before the age of 40 yr; 128 affected family members within eight families originating from one geographical area in Iceland have been identified (refs. 2 and 3; unpublished studies). Recently a similar autosomal dominant cerebral amyloid angiopathy has been described in The Netherlands (4). The histopathology of HCHWA brains is similar to that of the congophilic angiopathy associated with some cases of Alzheimer disease and cases of cerebral hemorrhage caused by sporadic congophilic angiopathy. In HCHWA there are no plaques or neurofibrillary tangles, and the amount of vascular amyloid is quantitatively much greater than in the two other forms of cerebral amyloid angiopathy (5, 6), making chemical extraction of the amyloid fibrils feasible. We have reported (7) the amino-terminal sequence of the amyloid fibrils obtained from the brain of patients dying of HCHWA. This paper presents the complete primary sequence and discusses its relationship to related proteins and its potential ...

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Section: Resultsmentioning

confidence: 99%

Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C).

Ghiso¹,

Jensson²,

Frangione³

1986

Proc. Natl. Acad. Sci. U.S.A.

282

142

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“…Only recently has the role of mammalian kininogens in the inhibition of cysteine proteinases been clearly established [27]; ra kin, rat kininogen (major acutephase protein) [30]; bo col CPI, bovine colostrum cysteine proteinasc inhibitor [31]; ch cys, chicken cystatin from egg white [32, 331; hu cys, human cystatin (y-trace) from plasma [34, 351; hu SAP, human salivary acidic protein [36]; hu ste, human stefin from granulocytes [37]; hu liv CPI, human liver cystatin B [38]; ra epi TPI, rat epidermal thiol proteinase inhibitor [39]; ra liv TPI, rat liver thiol proteinase inhibitor inhibitors revealed that two potential reactive sites represented by the pentapeptide Gln-Val-Val-Ala-Gly might be present in the human kininogen heavy chain. An extended region of 27 amino acids centered around the putative reactive sitc shows extensive sequence homologies between the heavy chains of human, rat and bovine kininogens (Fig.…”

Section: Homologq Between Human High-m Kininogen Und Mummuliun Cystmentioning

confidence: 99%

Completion of the primary structure of human high-molecular-mass kininogen. The amino acid sequence of the entire heavy chain and evidence for its evolution by gene triplication

et al. 1986

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The amino acid sequence of the heavy chain of human high-molecular-mass kininogen has been determined. It completes the primary structure of the high-M, kininogen molecule. The heavy chain contains 362, the total kininogen molecule 626 amino acid residues. Three carbohydrate side chains were found in the heavy chain, all of them N-glycosidically linked to asparagine, which is present in the acceptor sequon Asn-Xaa-Thr (or -Scr); one additional potential glycosylation site devoid of a sugar side chain is found at position 30.There is a high degree of homology between the heavy chains of human high-M, kininogen and bovine high-M, kininogen (74% identity), or rat T-kininogen (61%).Comparison of the primary structure of human high-M, kininogen with that of huinan low-M, kininogen predicted from its cDNA sequence, reveals that the heavy chains of the two human kininogens are completely identical. Two heavy chain segments believed to contain the reactive sites for cysteine proteinase inhibition show an extensive sequence homology with other mammalian cysteine proteinase inhibitors.Within the heavy chain of human high-M, kininogen are repetitive units strongly suggesting that the heavy chain of human kininogens has evolved from at least two ancestral units by a series of gene duplication and fusion events.High-molecular-mass (high-M,) kininogen is the larger type of kinin precursor molecule present in mammalian plasma and secretions (for recent reviews, see [l, 21). A variety of important physiological functions is served by the high-M , kininogen such as kinin delivery, inhibition of cysteine proteinases [3, 41, complexing of coagulation enzymes [5] and initiation of the endogenous coagulation pathway [6]. Human high-M, kininogen is a single-chain glycoprotein of apparent M , 114000 (as judged from gel electrophoresis [2]). Limited proteolysis of high-M, kininogen by plasma kallikrein releases the vasoactive kinin and generates a nicked kininogen molecule consisting of a heavy chain (H chain) of M , 63000 and a light chain (L chain) of M , 58000 interconnected via a single disulfide bridge [2]. The H chain portion contains two reactive sites which inhibit cysteine proteinases such as cathepsin L and papain with high affinity (approx. Ki 3 x 10-" M [4]). The L chain contains a unique histidine-rich portion which mediates the binding of the kininogen molecule to the surface of endothelial lesions [7]. In this way, high-M, kininogen which circulates in plasma in the form of a complex with prekallikrein and factor XI, places these enzymes on the surface in proximity to already bound factor XI1 during the contact phase activation, thereby triggering the intrinsic blood coagulation pathway [8].High-M, kininogen shares the kinin delivery and proteinase inhibition function with the second type of kininogen In a previous communication, we have presented the amino acid sequence of the light chain of huinan high-M, kininogen [ll]. Here we report on the total amino acid sequence of the heavy chain, thereby completing the primary ...

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“…HRGD2 was most homologous (22% identical) to human cystatin S [8] as well as other cystatins and HKHDS. The similarity of Fig.…”

mentioning

confidence: 99%

Histidine‐rich glycoprotein is evolutionarily related to the cystatin superfamily

Koide

Okada

1987

FEBS Letters

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A new member of the cystatin superfamily is introduced. Human plasma histidine-rich glycoprotein (HRG) was found to contain 2 cystatin-like sequences in tandem in the N-terminal region. Domain 1 (residues l-112) was most homologous to domain 1 of the heavy chain of human kininogen and domain 2 (residues 113-225) was most homologous to human cystatin S as well as other cystatins and domain 3 of the heavy chain of kininogen, suggesting that the cystatin domains of HRG may represent a hitherto unknown binary form (or intermediate molecule) composed of 2 cystatin domains, and evolutionarily intermediate between the cystatin and the kininogen families.

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Cystatin S: A Cysteine Proteinase Inhibitor of Human Saliva

Cited by 115 publications

References 0 publications

Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C).

Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C).

Completion of the primary structure of human high-molecular-mass kininogen. The amino acid sequence of the entire heavy chain and evidence for its evolution by gene triplication

Histidine‐rich glycoprotein is evolutionarily related to the cystatin superfamily

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