14. Proteins require signals to be transported through the pore

8.14 Proteins require signals to be transported through the pore

To be transported through the nuclear pore, a protein must have a special signal in its sequence. The most common motif responsible for import into the nucleus is called the nuclear localization signal (NLS). Its presence in a cytosolic protein is necessary and sufficient to sponsor import into the nucleus. Mutation of the signal can prevent the protein from entering the nucleus (Kalderon et al., 1984).

Figure 8.40 Nuclear localization signals have basic residues.

The summary of nuclear localization signals in Figure 8.40 shows that there is no apparent conservation of sequence of NLS signals; perhaps the shape of the region or its basicity are the important features. Many NLS sequences take the form of a short, rather basic stretch of amino acids. Often there is a proline residue to break α-helix formation upstream of the basic residues. Hydrophobic residues are rare. Some NLS signals are bipartite and require two separate short clusters (Robbins et al., 1991). Competition studies suggest that NLS sequences are interchangeable, suggesting that they are all recognized by the same import system.

Many exported proteins have a common type of signal that is necessary and sufficient for the protein to move from the nucleus to the cytosol. It is called an NES (nuclear export signal), and typically consists of an ~10 amino acid sequence. The only common feature in the NES sequences in different proteins is a pattern of conserved leucines (Fischer et al., 1995; Bogerd et al., 1996).

A protein may have both an NLS and an NES, the former used for its import into the nucleus, and the latter for its export. They may function constitutively, or their use can be regulated, for example, by association with other proteins that obscure or expose the relevant sequences (Michael and Choi, 1995).

Research

Bogerd, H. P. , Fridell, R. A. , Benson, R. E. , Hua, J. , and Cullen, B. R. (1996). Protein sequence requirements for function of the human T-cell leukemia virus type 1 Rex nuclear export signal delineated by a novel in vivo randomization-selection assay.. Mol. Cell Biol. 16, 4207-4214.

Fischer, U. , Huber, J. , Boelens, W. C. , Mattaj, I. W. , and Luhrmann, R. (1995). The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs.. Cell 82, 475-483.

Kalderon, D. , Richardson, W. D. , Markham, A. F. , and Smith, A. E. (1984). Sequence requirements for nuclear location of simian virus 40 large-T antigen.. Nature 311, 33-38.

Michael, W. M., Choi, M. and Dreyfuss, G. (1995). A nuclear export signal in hnRNP A1: a signal-mediated, temperature-dependent nuclear protein export pathway. Cell 83, 415-422.

Robbins, J. et al. (1991). Two interdependent basic domains in nucleoplasmin nuclear targeting sequence: identification of a class of bipartite nuclear targeting sequences. Cell 64, 615-623.