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Intracellular trafficking of MAN1, an integral protein of the nuclear envelope inner membrane

Departments of Medicine and of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA

^* Author for correspondence (e-mail: hjw14{at}columbia.edu )

Accepted 9 January 2002

MAN1 is an integral protein of the inner nuclear membrane that shares the LEM domain, a conserved globular domain of approximately 40 amino acids, with lamina-associated polypeptide (LAP) 2 and emerin. Confocal immuofluorescence microscopy studies of the intracellular targeting of truncated forms of MAN1 showed that the nucleoplasmic, N-terminal domain is necessary for inner nuclear membrane retention. A protein containing the N-terminal domain with the first transmembrane segment of MAN1 is retained in the inner nuclear membrane, whereas the transmembrane segments with the C-terminal domain of MAN1 is not targeted to the inner nuclear membrane. The N-terminal domain of MAN1 is also sufficient for inner nuclear membrane targeting as it can target a chimeric type II integral protein to this subcellular location. Deletion mutants of the N-terminal of MAN1 are not efficiently retained in the inner nuclear membrane. When the N-terminal domain of MAN1 is increased in size from 50 kDa to 100 kDa, the protein cannot reach the inner nuclear membrane. Fluorescence recovery after photobleaching experiments of MAN1 fused to green fluorescent protein show that the fusion protein is relatively immobile in the nuclear envelope compared with the endoplasmic reticulum of interphase cells, suggesting binding to a nuclear component. These results are in agreement with the `diffusion-retention' model for targeting integral proteins to the inner nuclear membrane.

Key words: Nuclear envelope, Inner nuclear membrane, LEM domain, Fluorescence recovery after photobleaching, ng, Membrane proteins, Muscular dystrophy

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