Targeting lamin proteins to the nuclear envelope: the role of CaaX box modifications.

Introduction ‘I’he nuclear lamina is a protein network lining the nucleoplasmic surface of the inner nuclear menibrane. I t is presumed to represent a karyoskeletal element important for nuclear envelope integrity and interphase chromatin organization (for reviews see [ 1, 21). Its major constituents. the nuclear lamins, are members of the intermediate filament (IF) protein family [3-51. On the basis of biochemical properties, structural criteria, and expression patterns, vertebrate lamins have been classified as either Aor &type. T w o structurally distinct ]{-type lamins (13, and I<?) are expressed in virtually all somatic cells. but expression of A-type lamins is developrnentally regulated, with little or no larnin A being expressed in undifferentiated cell types (reviewed in 16 I). During mitosis the nuclear lamina is transiently disassembled in response to hyperphosphorylation of lamin proteins 1710 ] ~ and recent results implicate the p.34”‘“ protein kinase in directly controlling this process 1 1 1-1 31. While Ibtype lamins remain associated with membranes throughout the cell cycle, A-type lamins are found in a soluble state in mitotic cells 17, 141. 1,amins share with cytoplasmic 11; proteins a tripartite organization in that they display a central a-helical rod domain. flanked by non-a-helical domains at the Nand C-terminal ends. I lowever, lamins are readily distinguished from cytoplasmic members of the IF Family by the presence of a nuclear localization signal (N1,S) and a C-terminal CaaX box (reviewed in [6, 15 1). ‘I’he former motif is necessary for nuclear transport 161, while the CaaX box is modified by isopreny1;ition. proteolytic trimming, and carboxyl methylation [ 1710 1. Such modifications occur not only on lamins, but also on certain yeast mating factors, rus proteins and many other (;TI’-hydrolysing (G-) proteins (reviewed in [ 20-23 I). ‘I’hese hydrophobic modifications appear t o represent a general mechanism for increasing the