| Feature | Protein motif | Protein domain | Remarks |
| Definition | A short, conserved sequence or structural pattern associated with a particular function | A larger, distinct region of a protein that can often fold into a stable three-dimensional structure and perform a specific function | A motif is generally a smaller feature within a protein, whereas a domain is a larger functional or structural unit |
| Typical size | Usually a few to ~20–30 amino acids, although some motifs can be larger | Commonly ~40–300+ amino acids | There is no absolute size boundary between motifs and domains |
| Structural independence | Usually does not form an independently stable structure | Often capable of forming an independently stable three-dimensional structure | Some motifs are defined primarily by sequence rather than by an independently folded structure |
| Functional role | Usually contributes to a specific molecular interaction, catalytic activity, localization, or regulation | Often provides a major biochemical, structural, or interaction function | Several motifs may cooperate within a single domain |
| Sequence conservation | Specific amino acids or a short sequence pattern are often highly conserved | Conservation can extend across much of the domain, reflecting structural and functional constraints | Domain conservation is often detected through sequence and structural similarity |
| Occurrence in proteins | May occur within a domain or in regions outside recognizable domains | A protein may contain one or multiple domains | A single protein can therefore contain many motifs and several domains |
| Three-dimensional structure | May represent a short structural feature, such as a loop or binding pattern, but need not fold independently | Usually has a characteristic three-dimensional fold | Structural motifs can also be components of larger domains |
| Functional independence | Usually cannot perform a complete biological function on its own | Frequently retains a recognizable function when present in another protein context | Some domains require interaction with other domains or proteins for full activity |
| Examples | Nuclear localization signal, ATP-binding motif, catalytic triad, Cys₂His₂ zinc-finger motif | Protein kinase domain, SH2 domain, immunoglobulin domain, WD40 domain | A protein kinase domain, for example, contains several conserved sequence motifs important for catalysis |
| Bioinformatics identification | Often identified using sequence patterns, profiles, or motif/signature databases | Commonly identified using profile Hidden Markov Models (HMMs), sequence similarity, structural information, or domain databases | PROSITE is particularly associated with signatures/patterns, whereas Pfam and SMART are widely used for domain identification |
| Evolutionary significance | A conserved motif can indicate preservation of a particular molecular function | Conserved domains often indicate an evolutionary and functional module shared among proteins | Domains can be recombined during evolution to generate proteins with different combinations of functions |
| Relationship to other features | Several motifs can occur within the same domain | A domain can contain multiple conserved motifs | This is an important distinction: motifs can be components of domains |
