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First published online March 2, 2004
doi: 10.1242/10.1242/jcs.01102

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Proteins that bind A-type lamins: integrating isolated clues

Department of Cell Biology, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA

View larger version (24K): [in a new window]   Fig. 1. Regions in lamins A and C to which partners bind. The structural domains (head, rod, tail) of prelamin A are shown. Exons 1-12 encoding residues 1-664 are numbered; the last residue encoded by each exon (except exon 11) is given above. The Ig-fold domain, which includes exons 8 and 9, is shaded gray. Residues 1-566 of lamin A and lamin C are identical. Unique lamin C tail residues 567-572 are produced by alternative mRNA splicing; thus the extreme C-terminal regions of lamins A and C may have distinct binding properties. The zigzag represents the farnesyl moiety on prelamin A; the farnesylated C-terminal peptide is normally removed by proteolytic cleavage after residue 646 (bold; dotted line) to generate mature lamin A. Colored bars indicate the region(s) in lamins A and C required for each named partner to bind, as detailed in Table 1 (e.g. actin can bind two different regions in the tail). For partners with question marks, the binding region in lamin A/C is unmapped. Based on current incomplete knowledge, interactions were loosely color-coded (top to bottom) as blue (architectural), orange (chromatin), yellow (gene regulation), pink (signaling) and green (unknown). Some partners (e.g. BAF) will continue to defy categorization until more is known about their functions.

View larger version (58K): [in a new window]   Fig. 2. Speculative cartoon to `integrate isolated clues', and stimulate thought. A few interactions described for A-type lamins in the text are illustrated here, speculatively, in the context of lamin filaments near the nuclear inner membrane (IM) or associated with chromatin. Integral membrane proteins nesprin 1 (Nesprin) and emerin (EM) are embedded at the IM. Many other lamin-binding IM proteins are not depicted. NPC, nuclear pore complex. NS, nucleosome. OM, nuclear outer membrane. (Top left) Emerin, representing all LEM-domain proteins, binds BAF. BAF and MOK bind lamins in vitro and inhibit Crx-dependent gene activation in vivo, implicating both proteins in lamin-dependent gene-regulation events. Not depicted are potential gene-regulatory complexes involving nuclear membrane proteins LAP2b (Nili et al., 2001; Foisner, 2003) or lamin B receptor (Östlund and Worman, 2003). Emerin has many direct binding partners including nesprin-1, lamins, actin (not depicted), BAF and several transcription regulators (not shown) (Bengtsson and Wilson, 2004). The number of distinct oligomeric complexes that include emerin is not known. (Top right) Lamin-binding enzyme 12(S)-lipoxygenase [12(S)-LOX] converts arachidonic acid (AA) to 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE]. We speculate that this reaction occurs in a signaling complex near the inner membrane, where 12(S)-HETE then activates lamin-bound protein kinase C (PKC), leading to phosphorylation of unknown target proteins. (Bottom center) Pairwise interactions, summarized in the text, suggest that one or multiple oligomeric gene-regulation complexes might be formed by LAP2, A-type lamins, retinoblastoma (Rb), E2F/DP heterodimers (gene-specific activators), chromatin-silencing histone deacetylase complex (HDAC), BAF and additional unidentified chromatin partners for LAP2 (Vlcek et al., 2002).

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