Mechanism by which $lacI^{d}$ is a dominant mutation, impairing the function of normal copies of the Lac Repressor

Question

Jacob-Monod model for the lac Operon was based on experiments using two strands of bacteria which constitutively expressed $\beta$-gal: $I^{c}$(mutation in the gene lacI , which encodes the repressor) and $O^{c}$(mutation in the operator, the site where the repressor binds).

$I^{c}$ mutants are usually recessive: the Lac Repressor cannot bind to the operator, however, if a wild-copy of the gene is present in a merodiploid, the inducible pattern of expression is restored, because the Lac Repressor acts in trans (that is, it will inhibit expression of both operons when lactose is not present).

However, I've read that there's a strain ($lacI^{d}$) which is dominant, so the expression is constitutive even in the presence of the normal repressor. According to the article linked, abnormal subunits may mix with normal subunits, resulting in a disfunctional tetramer, even if a wild type lacI is also present. In terms of protein structure, why some mutations may have this effect and be dominant while other mutations do not interfere with normal copies of the protein and are recessive?

Answer 1

The lac repressor act as a tetramere molecule and requires all 4 of the subunit to be able to bind DNA to act on the operon and repress β-galactosidase expression.

The "all 4" is the key here, if any of the 4 subunits is unable to bind DNA then the whole complex cannot attach to the operon. The lacI^d mutation produces a repressor subunit that cannot attach DNA, yet can tetramerize with other lac repressor subunits, therefore impeding WT subunits to bind the operon.

For your question on the protein structure. Mutations can occur at different locations in a gene and therefore impact different proteins domains. Proteins contain different type of domains, such as an active site for an enzyme or a binding sites for attaching to the DNA. A mutation might act on one of the domain while leaving others fully functional.

In your case this is exactly what happens, the mutation is in the protein region involved in binding DNA but does not affect the region involved in the protein-protein binding with other subunits.

Answer 2

Concerning the difference between dominant vs. recessive mutations, in general, recessive, or loss-of-function mutations, are much more frequent than dominant, or gain-of-function, mutations, because there are many different ways to "break" or inactivate a protein. For example, not every amino acid site has the potential to mutate to a residue with dominant phenotype, but most sites can mutate to a side chain that might destabilize, disrupt, etc. The lacId allele is a dominant loss-of-function (and so somewhat more complex than the simple explanation I just gave). It makes a so-called "poison product"

Answer 3

lacID is an example of a dominant-negative allele (or mutation) so the phenotype is visible in m/+ (the bacterial merodiploids are the prokaryotic version of heterozygotes), and therefore, by definition, dominant, however the phenotype (in this case constitutive expression of the lac operon) is the same as the loss-of-function phenotype (a complete knock-out, or deletion of the lac Repressor gene). If m/+ has the same phenotype as m/m it could be dose-sensitive, or the protein could be a multimer, or the mutant protein could titrate (or sequester) an interacting protein.