A structural assessment of the apo[a] protein of human lipoprotein[a]

Abstract

Apolipoprotein[a], the highly glycosylated, hydrophilic apoprotein of lipoprotein[a] (Lp[a]), is generally considered to be a multimeric homologue of plasminogen, and to exhibit atherogenic/thrombogenic properties. The cDNA-inferred amino acid sequence of apo[a] indicates that apo[a], like plasminogen and some zymogens, is composed of a kringle domain and a serine protease domain. To gain insight into possible positive functions of Lp[a], we have examined the apo[a] primary structure by comparing its sequence with those of other proteins involved in coagulation and fibrinolysis, and its secondary structure by using a combination of structure prediction algorithms. The kringle domain encompasses 11 distinct types of repeating units, 9 of which contain 114 residues. These units, called kringles, are similar but not identical to each other or to PGK4. Each apo[a] kringle type was compared with kringles which have been shown to bind lysine and fibrin, and with bovine prothrombin kringle 1. Apo[a] kringles are linked by serine/threonine- and proline-rich stretches similar to regions in immunoglobulins, adhesion molecules, glycoprotein Ib-alpha subunit, and kininogen. In comparing the protease domains of apo[a] and plasmin, apo[a] contains a region between positions 4470 and 4492 where 8 substitutions, 9 deletions, and 1 insertion are apparent. Our analysis suggests that apo[a] kringle-type 10 has a high probability of binding to lysine in the same way as PGK4. In the only human apo[a] polymorph sequenced to date, position 4308 is occupied by serine, whereas the homologous position in plasmin is occupied by arginine and is an important site for proteolytic cleavage and activation. An alternative site for the proteolytic activation of human apo[a] is proposed.

Suppression of Colorectal Cancer Liver Metastasis and Extension of Survival by Expression of Apolipoprotein(a) Kringles

“…Ten types of kringles homologous to plasminogen kringle 4, designated KIV-1 to KIV-10, and one kringle (KV) homologous to plasminogen kringle 5 are observed in apo(a). Each KIV domain is present as a single copy, with the exception of KIV-2, which varies in number from 3 to 42 between apo(a) alleles (10).…”

Inhibition of Angiogenesis and Angiogenesis-dependent Tumor Growth by the Cryptic Kringle Fragments of Human Apolipoprotein(a)

“…The kringle 4-like repeats of apo(a) are followed by a single copy of plasminogen kringle 5 (KV) and a protease region. The plasminogen kringle 4-like repeats of apo(a) (KIV) can be further classified into 10 different types, KIV-1 to KIV-10, on the basis of amino acid sequence (12). Each of these kringle domains, except KIV-2, is present in a single copy.…”

A Truncated Kringle Domain of Human Apolipoprotein(a) Inhibits the Activation of Extracellular Signal-regulated Kinase 1 and 2 through a Tyrosine Phosphatase-dependent Pathway

“…It consists of tandemly repeated kringle domains that closely resemble plasminogen kringle 4 (KIV), followed by sequences that are homologous to the kringle 5 (termed KV) and protease domains of plasminogen (6). The KIV domains of apo(a) can be classified into 10 types (designated types KIV-1 to KIV-10), based on amino acid sequence (7). Although the physiological and biochemical roles of apo(a) kringle domains remain to be elucidated, there exists some evidence suggesting that they can inhibit angiogenesis in vitro (8) and suppress tumor growth in vivo (9).…”