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Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Kringle domains (KD) are 70–80 amino acids long and are mostly present in blood plasma proteins (proteases, cofactors, growth factors, apolipoproteins). Around 39 KDs are found in human proteome. Structurally, KD comprises two antiparallel β-sheets, and three disulfide bonds. The core structure of KD is conserved among all the proteins containing KD domains. Around 40 amino acids constituting these surface exposed loops are highly variable and therefore are involved in interaction with various biomolecules such as other proteins, lipids, or some small molecules (Lee et al., 2010a). Lee et al. generated KD variants that are anatagonists for human TNFa. Additionally, they have also designed KD variants that are agonists of death receptor 4 (DR4) and death receptor 5 (DR5) with antitumor activity (Lee et al., 2010b). Further, Lee et al. generated bi-specific kringle domains that can bind to both DR4 and DR5. Kringle domains provide an advantage over other scaffolds for the development of bispecific scaffolds within a single domain (Lee et al., 2011).
Structure/Function Relationships of t-PA
Published in Cornelis Kluft, Tissue-Type Plasminogen Activator (t-PA): Physiological and Clinical Aspects, 1988
For a better understanding of the structure of t-PA, this enzyme should not only be compared with u-PA, but also with other proteases and proteins. In addition to the catalytic light chain, the domains of the heavy chain of t-PA are strikingly homologous to domains in a variety of other proteins (for reviews, see References 152 to 154). Table 3 summarizes the presently known occurrence of the finger domain, the growth factor domain, and the kringle domain — both inside and outside (!) the family of serine proteases. Recognition of common structures has not always led to recognition of common functional properties. For example, the role, if any, of the growth factor domains in proteases is still unknown. It is interesting that a part of t-PA (including the C-terminal part of the growth factor) is homologous to albumin and α-fetoprotein.155 The finger domains, at least in t-PA and fibronectin, are probably involved in fibrin-binding. Extrapolation of this function to factor XII suggests that interaction of factor XII and fibrin may be important. Although the exact function of the kringle domains is not yet known, the general impression is that they are involved in regulatory protein-protein interactions. In this connection it should be mentioned that kringles are homologous with the type II structures of the gelatin-binding region of fibronectin.156 In concert with this is the homology between both the gelatin-binding domain of fibronectin and kringle 2 of t-PA with PDC-109, a major protein in bovine seminal plasma of unknown function.157
Novel Peptide NT/K-CFY Derived from Kringle Structure of Neurotrypsin Inhibits Neovascularization
Published in Current Eye Research, 2021
Xieyi Yao, Chong Chen, Jian Zhang, Yupeng Xu, Shuyu Xiong, Qing Gu, Xun Xu, Yan Suo
It is known that the kringle domain is a conservative 80 amino acid residue-long structure and has emerged to play a role in neovascular inhibition.5,6 Being considered as a specific functional anti-angiogenic unit, the kringle domain provides important clues for the screening of novel drugs. Neurotrypsin (NT), also known as motopsin or prss12 is a multi-domain serine protease predominantly expressed in neurons of the cerebral cortex, hippocampus, and lateral amygdala.7,8 The 875 amino-acid long human NT consists of a proline-rich base segment at the N-terminus, followed by a kringle domain, four scavenger receptor cysteine-rich repeats (SRCR), and a trypsin-like serine protease domain at the C-terminus.7,8 NT participates in the processing of learned behaviors and long-term memory formation,9 and is associated with mental retardation.10 However, so far there have been no studies concerning its role in the area of anti-neovascularization. As a series of anti-angiogenic kringle domains have already been observed, we wondered whether the kringle structure of NT would have similar effects.
Lipoprotein(a) in atherosclerosis: from pathophysiology to clinical relevance and treatment options
Published in Annals of Medicine, 2020
Andreja Rehberger Likozar, Mark Zavrtanik, Miran Šebeštjen
Lipoprotein(a) (Lp(a)) was discovered in 1963 [1]; however, it appeared to be of little importance until it was shown that this particular lipoprotein is an independent causal risk factor for cardiovascular disease (CVD) [2]. Lp(a) consists of a low-density lipoprotein (LDL)-like particle that is bound to apolipoproteinB100 (apoB), which is then linked with apolipoprotein(a) (apo(a)). Apo(a) has a very similar structure to plasminogen, although while apo(a) has only two types of kringle domains, as IV and V, plasminogen has five types (I–V). The molecular structure of apo(a) is shown in Figure 1. These kringle domains are protein domains with large loops that are stabilised by disulphide bridges and that contain lysine binding sites, which allow plasminogen to bind fibrin. Another difference here is the numbers of kringle IV (KIV) subtypes; apo(a) has 10 KIV subtypes, while plasminogen has only one KIV subtype [3]. However, as apo(a) has a similar overall structure to plasminogen, it can interfere with fibrinolysis [4]. Due to these similarities, apo(a) either binds to fibrin or forms a complex with fibrin, plasminogen and tissue plasminogen activator (t-PA). The result of these two actions is decreased fibrinolysis, and thus increasing risk for thrombotic events.
Lipoprotein(a) in clinical practice: New perspectives from basic and translational science
Published in Critical Reviews in Clinical Laboratory Sciences, 2018
Corey A. Scipione, Marlys L. Koschinsky, Michael B. Boffa
In 1987 it was determined that apo(a) possessed a high degree of homology with the plasma zymogen, plasminogen, and thus it bears many of the same key features [17]. Plasminogen is composed of an amino-terminal tail domain, followed by five unique domains known as Kringles (denoted as KI-KV), and a trypsin-like serine protease domain on its carboxyl terminus. The protease domain is a target for plasminogen activators, tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA), that cleave plasminogen into the active enzyme, plasmin. Kringle domains, which have a tri-looped structure that contains three conserved disulfide binds are found predominantly in the proteins that mediate the coagulation and fibrinolysis pathways, where they generally serve as protein binding domains. In contrast to plasminogen, apo(a) completely lacks the plasminogen tail domain and contains individual copies of 10 subtypes of a plasminogen-like Kringle IV (KIV) domain, with the exception of apo(a) KIV subtype 2 (KIV2), which can vary in copy number from less than three to greater than 30 identical copies. This variation in KIV2 is the source of the isoform size heterogeneity found within the population, and is dictated by the size of the LPA allele – the gene encoding apo(a) – which has marked variability between individuals. Following the KIV domains, apo(a) contains domains similar to plasminogen KV and a protease-like domain. The serine protease-like domain in apo(a) has been rendered inactive by amino acid substitutions and a nine amino acid deletion in the N-terminus, such that plasminogen activators cannot recognize apo(a) as a substrate for activation [18].