Ubiquitin-Like Modifiers

Ubiquitin is the most widely recognised post-translation modifier that bonds to proteins, marking them for degradation in the proteasome. However, there are many other proteins that have similar properties and are grouped together as a family, referred to as ubiquitin-like modifiers.

These proteins have significant functions that affect the biological processes that occur on a molecular level. Additionally, they can cross-regulate because some proteins can be modified by several UBLs simultaneously, resulting in multiple different pathways of conjugation.

Common Characteristics

The family of ubiquitin-like modifiers are not always equal in regards to sequence, but share a similar 3D structure, folded shape and possess a C-terminal glycine residue. It is this glycine point that later becomes the reaction site with substrate proteins, accounting for the similarity in the way the bonds are formed.

It is the characteristic structural fold that forms the shape of the protein, referred to as the ubiquitin fold that truly distinguishes ubiquitin-like modifying proteins. This allows them to interact with substrate proteins in a similar name, earning them the group characteristic as a family.

Often when ubiquitin-like modifiers bond to substrate proteins, they affect certain properties of the substrate, such as its affinity for surrounding ligands or molecules.


Small ubiquitin-like modifier (SUMO) proteins are able to bond to substrate proteins a similar way to the ubiquitin protein. However, the action of SUMOs is often antagonistic to that of ubiquitin and can, in fact, stabilise the protein substrates and mark it antagonistically to ubiquitin.

As a result, proteins marked by SUMO proteins may have an altered function rather than be sent to the proteasome for degradation. For example, they may have a greater or lesser affinity for other molecules such as ligands, or alter the substrate protein location or stability.

Some examples of SUMO proteins include:

  • KAP1
  • PIAS2
  • PIAS 3
  • RanGAP1
  • RNF4
  • SENP1
  • SENP2
  • SUMO
  • SAE1/UBA2
  • SIM
  • SUMO1
  • SUMO2
  • SUMO2/3
  • SUMO2/3/4
  • SUMO 3
  • Poly-SUMO2
  • Di-SUMO2
  • SUMO3
  • Poly-SUMO3
  • Di-SUMO3
  • SUMO4
  • UBE21/UBC9
  • ZMIZ1/Zimp10


NEDDylation occurs via a process very similar to ubiquitination, although the process requires distinct E1 and E2 proteins.

Some examples of NEDD ubiquitin-like proteins include:

  • NEDD8
  • NEDD8 Activating Enzyme (APPBP1/UBA3)
  • NEDD8 Activating Enzyme (E1) Inhibitors
  • NEDp1/SENP8
  • NUB1
  • UBE2F
  • UBE2M/UBC12

ISGylation and UFMylation

ISG and UFM proteins also bond to substrate proteins in similarly to ubiquitin. Likewise, the result of ISGylation and UFMylation can have a range of effects according to the specific bonds and protein.

Some examples of ISG ubiquitin-like proteins include:

  • ISG15/UCRP
  • ISG15 Activating Enzyme/UBE1L
  • UBCH8

Some examples of UFM ubiquitin-like proteins include:

  • Ufc1
  • UFM1
  • UFM Activating Enzyme/UBA5

Other Ubiquitin-Like Modifiers

There are also some other ubiquitin-like modifiers that do not fit into any of the above classifications. These proteins include:

  • APG8
  • APG 12
  • FAT10
  • URM1
  • Hub1

This is not a complete list of all ubiquitin-like modifiers and new proteins that fit into this functional family may be discovered with continuing research.


Further Reading

Last Updated: Jul 20, 2023

Yolanda Smith

Written by

Yolanda Smith

Yolanda graduated with a Bachelor of Pharmacy at the University of South Australia and has experience working in both Australia and Italy. She is passionate about how medicine, diet and lifestyle affect our health and enjoys helping people understand this. In her spare time she loves to explore the world and learn about new cultures and languages.


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