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Is every tetramer thought to be a dimer of dimers? Because even if every subunit is unique in structure, it could be a heterodimer of heterodimers? Or is the term "dimer of dimers" reserved for something more specific like symmetric tetramers?

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    $\begingroup$ No, only if it's justified. $\endgroup$
    – Mithoron
    Feb 4 at 13:52
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    $\begingroup$ A dimer is an aggregate of two identical subunits, not necessarily connected in a symmetric fashion! "Heterodimer" is a somewhat unusual term. And a "dimer of dimers" must actually fit that description. $\ce{A + A3 <=> A4}$ does NOT, obviously. ?! $\endgroup$
    – Karl
    Feb 4 at 14:24
  • $\begingroup$ The jargon in my grad-lab was that a dimer of dimers has D2 symmetry while a tetramer could also refer to C4 symmetry. All of these would be homotetramers. Hemoglobin is a good example of a heterotetramer. The 4 protomers all have the same fold but slightly different sequence. See e.g. proteopedia.org/wiki/index.php/… and click on the "light-blue chains" link. $\endgroup$ Feb 4 at 18:33
  • $\begingroup$ biorxiv.org/content/10.1101/431288v1.full $\endgroup$ Jun 13 at 11:17
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Logic

A dimer of dimers implies that there are four units (2 x 2 = 4) somehow organized into two pairs. To be meaningful and not arbitrary, the units within pairs should somehow be related in a different way to each other than units in between pairs. Units within pairs should probably also connected in some way.

Is every tetramer thought to be a dimer of dimers?

No, not by that logic. The four branches of a multiplication sign ($\times$) don't look like dimers of dimers because of the four-fold symmetry. On the other hand, it would make perfect sense to talk of a dimer of dimers for the protein quaternary structure depicted below because the protomers of like color have a different (and larger) interface than the one of unlike color.

enter image description here

Source: https://www.biorxiv.org/content/10.1101/431288v1.full

If a structure containing 4 units always falls apart into the same 2 pairs of units, you could also speak of a dimer of dimers. So if a complex ABCD always falls apart this way

$$\ce{ABCD -> AB + CD}$$

but not e.g. that way

$$\ce{ABCD ↛ AC + BD},$$

speaking of a dimer of dimer would make sense.

Jargon

The jargon in my grad-lab was that a dimer of dimers has D$_2$ symmetry while a tetramer could also refer to C$_4$ symmetry (or some other arrangement lacking 2-fold axes). Strictly speaking, all of these would be homotetramers but you could use this for protomers that are unequal but highly similar. Hemoglobin is a good example of a heterotetramer. The 4 protomers all have the same fold but there are two sequences, represented twice. You could summarize this by saying hemoglobin has an $\alpha_2 \beta_2$ quaternary structure. See e.g. this Proteopedia page and click on the "light-blue chains" link. The symmetry could be described as dimer of dimers, even though logic might tell you not to. Certainly, there is no evidence for hemoglobin falling apart into separate $\alpha_2 $ and $\beta_2$ parts.

Because even if every subunit is unique in structure, it could be a heterodimer of heterodimers?

Yes, if there is a reason to group the four units into two pairs in a specific way.

Or is the term "dimer of dimers" reserved for something more specific like symmetric tetramers?

There is no central agency that regulates how scientists talk and write about their objects of interest. So you will find inconsistent language until someone writes a textbook or review paper from which most people adopt the usage of a technical term.

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