Structural principles of leucine‐rich repeat (LRR) proteins

Enkhbayar, Purevjav; Kamiya, Masakatsu; Osaki, Mitsuru; Matsumoto, Takeshi; Matsushima, Norio

doi:10.1002/prot.10605

Cited by 200 publications

(173 citation statements)

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“…Although the 3 dimensional structure of the 83 kDa subunit has not been determined, the other known LRR structures adopt an overall horseshoe shape with a curved β-sheet lining the inner, concave surface and other repeated secondary structures, such as α-helix or β-turn, flanking the outer circumference [47,48]. Homology modeling of the 83 kDa subunit was accomplished using the ESyPred3D program [49], yielding a structure within the LRR domain similar to those of other LRR proteins (Fig.…”

Section: Structure Of the 83 Kda Subunitmentioning

confidence: 99%

“…platelet GPIb, GP V and GP IX, proteoglycans, RNAse inhibitor, luteinizing hormone receptor, oligodendrocyte/myelin glycoprotein and U2 snRNP-A′) [44][45][46]. The LRR motif has now been found in over 2000 proteins from a variety of species [47,48] and these proteins comprise a subset of the larger "solenoid protein" superfamily [48]. Although very few members of this family have been crystallized, the LRR forms a structure important for mediating binding interactions [47,48].…”

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confidence: 99%

“…The LRR motif has now been found in over 2000 proteins from a variety of species [47,48] and these proteins comprise a subset of the larger "solenoid protein" superfamily [48]. Although very few members of this family have been crystallized, the LRR forms a structure important for mediating binding interactions [47,48].The primary sequence of the 83 kDa subunit can be divided into 3 major domains with the following features ( Fig. 1B): 1. a 52 residue N-terminal domain that contains a cysteine-rich LRR N-flanking region (amino acids 1-27); 2. a 312 residue central domain that consists of 13 tandem leucine-rich repeats of 24 residues each (amino acids 53-364); 3. a C-terminal domain of 145 residues that contains a 26 residue cysteine-rich LRR C-flanking region (amino acids 400 -425).…”

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confidence: 99%

“…Although very few members of this family have been crystallized, the LRR forms a structure important for mediating binding interactions [47,48].…”

mentioning

confidence: 99%

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Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Skidgel

Erdös

2007

International Immunopharmacology

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Human carboxypeptidase N (CPN) was discovered in the early 1960s as a plasma enzyme that inactivates bradykinin and was identified 8 years later as the major "anaphylatoxin inactivator" of blood. CPN plays in important role in protecting the body from excessive buildup of potentially deleterious peptides that normally act as local autocrine or paracrine hormones. This review summarizes the structure, enzymatic properties and function of this important human enzyme, including insights gained by the recent elucidation of the crystal structure of the CPN catalytic subunit and structural modeling of the non-catalytic regulatory 83 kDa subunit. We also discuss its physiological role in cleaving substrates such as kinins, anaphylatoxins, creatine kinase, plasminogen receptors, hemoglobin and stromal cell-derived factor-1α (SDF-1α). HistoryCarboxypeptidases were initially isolated from pancreatic extracts and so were associated with protein and peptide degradation in the digestive tract [1][2][3][4]. However, work beginning in the early 1960's by Erdös and Sloane [5] revealed the presence of a novel carboxypeptidase in the blood that plays a regulatory role by inactivating bradykinin via removal of its C-terminal Arg residue. (Subsequent research some 2 decades later led to the discovery of a second kinin B 1 receptor activated by the carboxypeptidase metabolite that is its endogenous agonist -see below). Initially it was assumed that the enzyme represents a circulating form of pancreatic carboxypeptidase B, but this was disproved by the characterization of its enzymatic properties [5][6][7][8], which was later borne out by biochemical studies, sequence analysis [9][10][11][12][13][14][15] and ultimately X-ray crystallography [16]. To differentiate it from the pancreatic enzyme, it was named carboxypeptidase N (CPN; EC 3.4.17.3) and was the first member of a family of carboxypeptidases now known as the regulatory or CPN/E subfamily of metallocarboxypeptidases [17][18][19]. It has since been re-discovered many times as other substrates were found and so has acquired aliases such as creatine kinase conversion factor, plasma carboxypeptidase B, arginine carboxypeptidase, lysine carboxypeptidase and protaminase [8,17,20,21]. The most notable was the finding by Bokisch and Müller-Eberhard in 1969 -70 [22,23] that the human plasma "anaphylatoxin inactivator" is identical with CPN. This finding explains our interest in the work of Dr. Tony Hugli, who has made many seminal contributions to the understanding of the structure and function of anaphylatoxins [24][25][26][27]. In Send Correspondence and Proofs To: Randal A. Skidgel, PhD, Dept. of Pharmacology (M/C 868), Univ. of Illinois College of Medicine, 835 S. Wolcott, Chicago, IL 60612, Phone: 312-996-9179, FAX: 312-996-1648, EMAIL: E-mail: rskidgel@uic.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript w...

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Section: Structure Of the 83 Kda Subunitmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…Although very few members of this family have been crystallized, the LRR forms a structure important for mediating binding interactions [47,48].…”

mentioning

confidence: 99%

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Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Skidgel

Erdös

2007

International Immunopharmacology

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“…This F-box motif is approximately 50 amino acids long located at the amino-terminus and was named after the presence of this motif in mammalian cyclin F protein [5,10,11]. The carboxyl-terminal part of the F-box proteins usually consists of substrate-binding domains of various types, such as Trp-Asp (WD) repeats and leucine-rich repeats (LRR), both of which have been demonstrated to bind to phosphorylated substrates [12][13][14]. Depending on the motifs at the carboxyl-terminus, F-box proteins are categorized into three major families: the FBW family contains F-box proteins with WD repeats whereas those from the FBL family contain LRRs.…”

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confidence: 99%