# AP1G1

## Overview
AP1G1 is a gene located on human chromosome 16 that encodes the protein adaptor related protein complex 1 subunit gamma 1 (AP-1 γ1 subunit). This protein is a component of the adaptor protein complex 1 (AP-1), which is involved in the formation of clathrin-coated vesicles and plays a crucial role in intracellular trafficking, specifically in the sorting of proteins between the trans-Golgi network and endosomes. The AP-1 complex, including the γ1 subunit, is essential for the selective transport and localization of membrane proteins, which is vital for cellular function and homeostasis. Mutations in the AP1G1 gene can lead to various developmental and physiological abnormalities, highlighting its importance in human biology (Johnson2016A; Usmani2021De).

## Structure
The molecular structure of the AP1G1 protein, encoded by the AP1G1 gene, is complex and involves several distinct domains that are crucial for its function in protein sorting within the cell. The AP1G1 protein includes a gamma-adaptin subunit, which is part of the larger AP-1 complex. This subunit is predicted to have four transmembrane domains followed by an alpha adaptin C2 domain at the carboxy terminus, which is known to bind clathrin and other receptors in coated vesicles (Usmani2021De). 

The gamma-1 adaptin also contains a PI4P binding site critical for its membrane association and a proline-rich flexible linker region that allows flexibility in the positioning of the globular C-terminal domain. This C-terminal 'ear' domain is essential for recruiting additional coat proteins at the site of clathrin-coated vesicle formation (Zizioli2017γ2). 

The AP1G1 protein interacts with various accessory proteins either directly or via other AP-1 subunits, although detailed information on the primary, secondary, tertiary, or quaternary structures of AP1G1, including prominent folds and common post-translational modifications, is not provided in the available literature (Usmani2021De).

## Function
The AP1G1 gene encodes the gamma-1 adaptin subunit of the adaptor protein complex 1 (AP-1), which is integral to the formation of clathrin-coated vesicles involved in intracellular protein sorting and trafficking. This complex is essential for the selective transport of proteins between the trans-Golgi network (TGN) and endosomes, playing a critical role in cellular organization and function (Johnson2016A; Usmani2021De). AP1G1 is particularly important in the sorting of membrane proteins, including the recycling of transferrin receptors, which is crucial for maintaining iron homeostasis in cells (Usmani2021De).

In neurons, AP1G1 helps in the polarized localization of somatodendritic proteins, which is vital for proper neuronal function and development (Usmani2021De). The protein is also involved in the formation of specialized structures like apicosomes in human pluripotent stem cell cysts, which are necessary for lumen formation and the establishment of the apical surface during and after mitosis (Wang2021Spatially).

Mutations in AP1G1 can lead to severe developmental and physiological abnormalities, demonstrating its essential role in vertebrate development and cellular homeostasis (Mignani2023Deficiency). The gene's function is so critical that its absence or malfunction can lead to a variety of disease phenotypes, termed adaptinopathies, which include a range of inherited disorders affecting intracellular vesicular traffic (Mignani2023Deficiency).

## Clinical Significance
Mutations in the AP1G1 gene are linked to a spectrum of neurodevelopmental disorders (NDDs) characterized by developmental delay, intellectual disability, and epilepsy. These disorders have been identified in diverse populations, with both bi-allelic and de novo heterozygous variants reported. Specific mutations, such as missense and frameshift variants, are predicted to disrupt the protein's function, potentially leading to altered protein folding, interactions, and cellular localization, which can affect critical cellular processes and contribute to the observed clinical symptoms (Usmani2021De).

In addition to neurodevelopmental impacts, AP1G1 mutations have been associated with other severe inherited disorders. Animal models have provided insights into the gene's role in development and disease. For instance, mice with a null mutation in AP1G1 exhibit early post-fertilization lethality, while specific hypomorphic mutations lead to abnormalities in multiple organs such as the inner ear, retina, thyroid, and testes, indicating the gene's essential role in the proper function of these tissues (Johnson2016A).

These findings underscore the critical role of AP1G1 in human development and its potential link to a range of clinical phenotypes, highlighting the importance of this gene in medical genetics and the potential for targeted therapeutic strategies.

## Interactions
AP1G1, a subunit of the adaptor protein complex 1, is involved in several critical protein-protein interactions that are essential for cellular processes such as protein sorting and vesicular transport. AP1G1 forms a heterotrimeric molecular complex with ASCT2 and EGFR, which is significant in the context of cetuximab-mediated downregulation of the ASCT2-EGFR complex through EGFR endocytosis (Tao2017AP1G1). This interaction does not depend on the inhibition of EGFR tyrosine kinase activity by cetuximab, highlighting a unique regulatory mechanism mediated by AP1G1 (Tao2017AP1G1).

Additionally, AP1G1 interacts with various subunits within the AP-1 complex itself, including the sigma-type subunit AP1S1, which is implicated in diseases like MEDNIK syndrome (Johnson2016A). This interaction underscores AP1G1's role in the functional integrity of the AP-1 complex, crucial for the sorting and targeting of membrane proteins.

AP1G1 also plays a role in the sorting and transport of cadherins, particularly E-cadherin, essential for the formation and function of adherens junctions in cells. This interaction is crucial for maintaining cell polarity and is involved in the polarized sorting of somatodendritic proteins and synaptic vesicle protein recycling in neurons (Mignani2023Deficiency). These interactions collectively demonstrate AP1G1's broad involvement in cellular trafficking and signal transduction pathways, impacting various cellular functions and developmental processes.


## References


[1. (Wang2021Spatially) Sicong Wang, Chien-Wei Lin, Amber E. Carleton, Chari L. Cortez, Craig Johnson, Linnea E. Taniguchi, Nikola Sekulovski, Ryan F. Townshend, Venkatesha Basrur, Alexey I. Nesvizhskii, Peng Zou, Jianping Fu, Deborah L. Gumucio, Mara C. Duncan, and Kenichiro Taniguchi. Spatially resolved cell polarity proteomics of a human epiblast model. Science Advances, April 2021. URL: http://dx.doi.org/10.1126/sciadv.abd8407, doi:10.1126/sciadv.abd8407. (20 citations) 10.1126/sciadv.abd8407](https://doi.org/10.1126/sciadv.abd8407)

[2. (Usmani2021De) Muhammad A. Usmani, Zubair M. Ahmed, Pamela Magini, Victor Murcia Pienkowski, Kristen J. Rasmussen, Rebecca Hernan, Faiza Rasheed, Mureed Hussain, Mohsin Shahzad, Brendan C. Lanpher, Zhiyv Niu, Foong-Yen Lim, Tommaso Pippucci, Rafal Ploski, Verena Kraus, Karolina Matuszewska, Flavia Palombo, Jessica Kianmahd, Julian A. Martinez-Agosto, Hane Lee, Emma Colao, M. Mahdi Motazacker, Karlla W. Brigatti, Erik G. Puffenberger, S. Amer Riazuddin, Claudia Gonzaga-Jauregui, Wendy K. Chung, Matias Wagner, Matthew J. Schultz, Marco Seri, Anneke J.A. Kievit, Nicola Perrotti, J.S. Klein Wassink-Ruiter, Hans van Bokhoven, Sheikh Riazuddin, and Saima Riazuddin. De novo and bi-allelic variants in ap1g1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy. The American Journal of Human Genetics, 108(7):1330–1341, July 2021. URL: http://dx.doi.org/10.1016/j.ajhg.2021.05.007, doi:10.1016/j.ajhg.2021.05.007. (23 citations) 10.1016/j.ajhg.2021.05.007](https://doi.org/10.1016/j.ajhg.2021.05.007)

[3. (Johnson2016A) Kenneth R. Johnson, Leona H. Gagnon, and Bo Chang. A hypomorphic mutation of the gamma-1 adaptin gene (ap1g1) causes inner ear, retina, thyroid, and testes abnormalities in mice. Mammalian Genome, 27(5–6):200–212, April 2016. URL: http://dx.doi.org/10.1007/s00335-016-9632-0, doi:10.1007/s00335-016-9632-0. (18 citations) 10.1007/s00335-016-9632-0](https://doi.org/10.1007/s00335-016-9632-0)

[4. (Tao2017AP1G1) Xiaoan Tao, Yang Lu, Songbo Qiu, Yi Wang, Jun Qin, and Zhen Fan. Ap1g1 is involved in cetuximab-mediated downregulation of asct2-egfr complex and sensitization of human head and neck squamous cell carcinoma cells to ros-induced apoptosis. Cancer Letters, 408:33–42, November 2017. URL: http://dx.doi.org/10.1016/j.canlet.2017.08.012, doi:10.1016/j.canlet.2017.08.012. (35 citations) 10.1016/j.canlet.2017.08.012](https://doi.org/10.1016/j.canlet.2017.08.012)

[5. (Mignani2023Deficiency) Luca Mignani, Nicola Facchinello, Marco Varinelli, Elena Massardi, Natascia Tiso, Cosetta Ravelli, Stefania Mitola, Peter Schu, Eugenio Monti, Dario Finazzi, Giuseppe Borsani, and Daniela Zizioli. Deficiency of ap1 complex ap1g1 in zebrafish model led to perturbation of neurodevelopment, female and male fertility; new insight to understand adaptinopathies. International Journal of Molecular Sciences, 24(8):7108, April 2023. URL: http://dx.doi.org/10.3390/ijms24087108, doi:10.3390/ijms24087108. (2 citations) 10.3390/ijms24087108](https://doi.org/10.3390/ijms24087108)

[6. (Zizioli2017γ2) Daniela Zizioli, Constanze Geumann, Manuel Kratzke, Ratnakar Mishra, Guiseppe Borsani, Dario Finazzi, Ermes Candiello, and Peter Schu. Γ2 and γ1ap-1 complexes: different essential functions and regulatory mechanisms in clathrin-dependent protein sorting. European Journal of Cell Biology, 96(4):356–368, June 2017. URL: http://dx.doi.org/10.1016/j.ejcb.2017.03.008, doi:10.1016/j.ejcb.2017.03.008. (15 citations) 10.1016/j.ejcb.2017.03.008](https://doi.org/10.1016/j.ejcb.2017.03.008)