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The Journal of Lipid Research, Vol. 40, 654-664, April 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

Phospholipid transfer protein (PLTP) causes proteolytic cleavage of apolipoprotein A-I

Correspondence to: M. Jauhiainen

Plasma phospholipid transfer protein (PLTP) is a factor that plays an important role in HDL metabolism. In this study we present data suggesting that PLTP has an inherent protease activity. After incubation of HDL₃ in the presence of purified plasma PLTP, the d < 1.25 g/ml particles (fusion particles) contained intact 28.2 kDa apoA-I while the d > 1.25 g/ml fraction (apoA-I-PL complexes) contained, in addition to intact apoA-I, a cleaved 23 kDa form of apoA-I. Purified apoA-I was also cleaved by PLTP and produced a similar 23 kDa apoA-I fragment. The cleavage of apoA-I increased as a function of incubation time and the amount of PLTP added. The process displayed typically an 8–10 h lag or induction period, after which the cleavage proceeded in a time-dependent manner. This lag-phase was necessary for the development of the cleavage activity during incubation at 37°C. The specific apoA-I cleavage activity of different PLTP preparations varied between 0.4–0.8 µg apoA-I degraded/h per 1000 nmol per h of PLTP activity. The 23 kDa apoA-I fragment reacted with monoclonal antibodies specific for the N-terminal part of apoA-I, indicating that the apoA-I cleavage occurred in the C-terminal portion. The apoA-I cleavage products were further characterized by mass spectrometry. The 23 kDa fragment yielded a mass of 22.924 kDa, demonstrating that the cleavage occurs in the C-terminal portion of apoA-I between amino acid residues 196 (alanine) and 197 (threonine). The intact apoA-I and the 23 kDa fragment revealed identical N-terminal amino acid sequences. The cleavage of apoA-I could be inhibited with APMSF and chymostatin, suggesting that it is due to a serine esterase-type of proteolytic activity. Recombinant PLTP produced in CHO cells or using the baculovirus-insect cell system caused an apoA-I cleavage pattern identical to that obtained with plasma PLTP.

The present results raise the question of whether PLTP-mediated proteolytic cleavage of apoA-I might affect plasma HDL metabolism by generating a novel kinetic compartment of apoA-I with an increased turnover rate.—Jauhiainen, M., J. Huuskonen, M. Baumann, J. Metso, T. Oka, T. Egashira, H. Hattori, V. M. Olkkonen, and C. Ehnholm. Phospholipid transfer protein (PLTP) causes proteolytic cleavage of apolipoprotein A-I. J. Lipid Res. 1999. 40: 654– 664.

Supplementary key words: phospholipid transfer protein, apolipoprotein A-I, proteolytic activity, HDL metabolism

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