Positive inside rule

The molecular basis of the positive-inside rule is unknown. However, negatively charged phospholipids can control the membrane protein topology, suggesting part of the mechanism (van Klompenburg et al., 1997). 

Predictions of membrane protein structure are in part based on the positive-inside rule which states that positively charged lysine and arginine residues will not pass through a membrane but will remain on the negatively charged cytoplasmic surface. Often, N-terminal parts of a protein will pass through a... 

Andersson, H., and von Heijne, G. (1994). Membrane protein topology effects of A/xH+ on the translocation of charged residues explain the positive inside rule. EMBO J. 13, 2267-2272. 

Gavel, Y, Steppuhn,J., Herrmann, R., and von Heijne, G. (1991). The positive-inside rule applies to thylakoid membrane proteins. FEBS Lett. 282, 41-46. 

Rojo, E. E., Guiard, B., Neupert, W., and Stuart, R. A. (1999). N-terminal tail export from the mitochondrial matrix—adherence to the prokaryotic positive-inside rule of membrane protein topology./. Biol. Chem. 274, 19617-19622. 

Based on statistical analysis and experimental determination, the cytoplasmic extramembrane domains connecting transmembrane domains predominantly carry a positive charge in contrast to the remaining extramembrane domains that are either neutral or negative (positive inside rule) [24]. Although amino acid sequence determines membrane protein topology, the sequence is encoded for a specific membrane lipid environment as has been demonstrated for the secondary transport proteins of E. coli. Reducing the net positive... 

In some cases, the prediction that can now be obtained by means of the pref method (2.0 version) is sufficient to correct the error in the number and location of transmembrane segments and consequently the error in the topology of the membrane protein. However, for some other proteins it is necessary to use the positive inside rule, similarity with related proteins as well as predictions obtained by other methods. 

Figure 4. Proposed topological model of cytochrome o ubiquinol oxidase from E. coli (cyoe ecoli). The topological model of protein cyoe ecoli is obtained only on the basis of the AP(X) profile acquired by means of the pref mediod (version 2.0) and the positive inside rule. Two transmembrane segments that are predicted in this report and that have not been predicted earlier (Ref. 68) are shown in boldface. Each amino acid residue is given in one-letter code (.see Section 5.3.3).

It has been pointed out that the swiss-prot data bank includes a certain number of membrane proteins for which the structure is not quite reliably determined, in part because older methods were used to determine the location and number of transmembrane segments. These older methods are less reliable because they were trained on a smaller sets of proteins. Hence, we suggest that it is necessary to use new and better methods for detecting these defective topologies in order to carry out additional research on them with the aim to obtain their more accurate structures and topologies. In the present report we have shown one of possible ways to carry out such a procedure and this has been illustrated using several examples. In this we also used the positive inside rule, predictions on similar proteins, and predictions obtained by other methods. 

G. von Heijne, Membrane protein structure prediction. Hydrophobicity analysis and the positive- inside rule, /. Mol. Biol. 225, 487 94 (1992). 

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